Devices, methods and systems for collecting material from a breast duct

ABSTRACT

The invention provides methods, devices and systems for collecting breast ductal fluid comprising cellular material and other useful markers for analysis. The methods typically comprise access of at least one breast duct and collecting materials from that duct separate from all other ducts in the breast. The devices comprise ductal access devices that provide the opportunity to collect fluid from a single duct separate from all the other ducts in the breast. The systems employ the methods and devices that used together provide systems for analysis of a breast condition in a patient specific to accessed breast ducts. The methods, devices and systems are particularly useful for indentification of breast precancer or cancer in patient.

CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application claims the benefit of each of the followingprovisional applications under 37 CFR §1.78: No. 60/114,048, filed onDec. 28, 1998; No. 60/134,613, filed on May 18, 1999; No. 60/143,476,filed on Jul. 12, 1999; No. 60/143,359, filed on Jul. 12, 1999; and No.60/______ (attorney docket no. 18612-003100), filed on Dec. 14, 1999.The full disclosures of each these applications are incorporated hereinby reference.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The field of this invention is devices, methods and systems forcollecting breast duct fluid from humans.

[0004] 2. Description of the Background Art

[0005] For several decades significant members of the medical communitydedicated to studying breast cancer have believed and shown that thecytological analysis of cells retrieved from nipple discharge from thebreast milk ducts can provide valuable information leading to aidentifying patients at risk for breast cancer. Indeed Papanicolaouhimself contributed to the genesis of such a possibility of a “Pap”smear for breast cancer by analyzing the cells contained in nippledischarge. See Papanicolaou et al, “Exfoliative Cytology of the HumanMammary Gland and Its Value in the Diagnosis of Cancer and OtherDiseases of the Breast” Cancer (1958) March/April 377-409. See alsoPetrakis, “Physiological, biochemical, and cytological aspects of nippleaspirate fluid”, Breast Cancer Research and Treatment 1986; 8:7-19;Petrakis, “Studies on the epidemiology and natural history of benignbreast disease and breast cancer using nipple aspirate fluid” CancerEpidemiology, Biomarkers and Prevention (January/February 1993) 2:3-10;Petrakis, “Nipple Aspirate Fluid in epidemiological studies of breastdisease”, Epidemiologic Reviews (1993) 15:188-195. More recently,markers have also been detected in nipple fluid. See Sauter et al,“Nipple aspirate fluid: a promising non-invasive method to identifycellular markers of breast cancer risk”, British Journal of Cancer76(4):494-501 (1997). The detection of CEA in fluids obtained by anipple blot is described in Imayama et al. (1996) Cancer 78: 1229-1234.

[0006] Breast cancer is believed to originate in the lining of a singlebreast milk duct in the breast; and additionally human breasts arebelieved to contain from 6 to 8 of these ducts. See Sartorius, JAMA 224(6): 823-827 (1973). Sartorious describes use of hair-like single lumencatheters that are inserted into breast ducts using an operatingmicroscope and the ducts were flushed with saline solution as describedin Cassels, D Mar. 20^(th), 1973, The Medical Post, article entitled“New tests may speed breast cancer detection”. Sartorius et al, Contrastductography for recognition and localization of benign and malignantbreast lesions: an improved technique. pp. 281-300. In: Logan WW, ed.BREAST CARCINOMA New York, Wiley, 1977. After the fluid was infused, thecatheter was removed because it was too small to collect the fluid, thebreast was squeezed and fluid that oozed onto the nipple surface wasremoved from the surface by a capillary tube. Similarly, Love andBarsky, “Breast-duct endoscopy to study stages of cancerous breastdisease”, Lancet 348(9033):997-999, 1996 describes cannulating breastducts with a single lumen catheter and infusing a small amount ofsaline, removing the catheter and squeezing to collect the fluid thatreturns on the nipple surface. The use of a rigid 1.2 mm ductscope toidentify intraductal papillomas in women with nipple discharge isdescribed in Makita et al (1991) Breast Cancer Res Treat 18: 179-188. Itwould be advantageous to develop methods and devices to collect theductal fluid from within the duct.

[0007] Galactography, or contrast ductography has for years locatedbreast ducts based on spontaneous nipple discharge, infused the ducts(using cannulas for this purpose) with contrast dye solutions, and takenx-ray pictures to determine the source of the discharge within the duct.See generally, The Breast: Comprehensive Management of Benign andMalignant Breast Diseases, Bland and Copeland eds. W.B. Saunders Co.Philadelphia Pa. 1991 pages 61-67.

[0008] Method and kits for obtaining fluid and cellular material frombreast ducts Ser. No. 09/067,661 filed Apr. 28, 1998, and its CIP09/301,058 filed Apr. 28, 1999 describe and claim infusing a smallamount of fluid into the duct and collecting the fluid using a catheter.It would be beneficial to optimize the cells and fluid collected fromthis procedure.

[0009] U.S. Ser. No. 60/143,359 filed Jul. 12, 1999 describes and claimsa multilumen catheter for collection of infused fluid. U.S. Ser. No.60/143,476 filed Jul. 12, 1999 describes and claims devices and methodsfor accessing the lactiferous sinus of a breast duct. U.S. Ser. No.60/122,076 filed Mar. 1, 1999 describes devices, methods and kits foraccessing more than one breast duct at a time for delivering and/orretrieving agents or materials to and from more than one breast duct atthe same time. Related applications are U.S. Ser. No. 60/143,476 andSer. No. 60/143,359 both filed Jul. 12, 1999 and Ser. No. 60/134,613filed May 18, 1999, and Ser. No. 60/114,048 filed Dec. 28, 1998, all ofwhich are herein incorporated by reference in their entirety.

[0010] Osmotic agents including sugars that are poorly absorbed, forexample lactulose or sorbitol, have been used as laxatives. See THEMERCK MANUAL OF MEDICAL INFORMATION, Berkow, Beers and Fletcher Eds,1997 Merck Res. Lab., Whitehouse Station, N.J. pp. 522-523. The osmoticagent mannitol is available as an injectable, 25% (Physicians DeskReference 1996) for a variety of indications (e.g. renal insufficiency,congestive heart failure). A mixture of sorbitol and mannitol iscompared to distilled water as an irrigant during transurethralprostatectomy in Sargin et al, (1997) Int Urol Nephrol 29:575-80.Intracranial pressure therapy has been provided by solutions ofmannitol, sorbitol or glycerol as described in Treib et al, (1998) EurNeurol 40: 212-219. Osmotherapy for increased intracranial pressurecomparing the use of mannitol and glycerol is discussed in Biestro etal, (1997) Acta Neurochir (Wien) 138: 725-32; discussion 732-3. Mannitoltherapy for renal conditions is described generally in Better et al,(1997) Kidney Int 52:886-894, and use of the osmotic diuretic mannitolfor renal protection is analyzed in Visweswaran et al, (1997) J Am SocNephrol 8: 1028-33. Use of mannitol during cardiac catheterization isdescribed in Willerson et al, (1975) Circulation 51:1095-1100 andKurnick et al, (1991) Am J Kidney Dis 17: 62-8. The osmotic effects ofpolyethylene glycol are discussed in Schiller et al, (1988)Gastroenterology 94: 933-41. Raffinose is used for peritoneal dialysisas described in Kohan et al (1998) J Lab Clin Med 131: 71-6.

[0011] Relevant Literature

[0012] Hou et al, “A simple method of Duct Cannulation and Localizationfor Galactography before Excision in Patients with Nipple Discharge.”Radiology 1995; 195; 568-569 describes injecting a “small volume ofsterile, water soluble contrast material . . . (0.5 ml-2.0 ml) . . . thecatheter was taped on the breast or nipple . . . the contrast materialwas aspirated with the same syringe and gentle manual pressure wasexerted on the breast to expel the opaque medium.”

[0013] The use of a 0.4 mm flexible scope to investigate nippledischarge is described in Okazaki et al (1991) Jpn J. Clin. Oncol.21:188-193 in which before the fiberoptic ductoscopy “a lacrimal cannulawas inserted [into the duct] for ductal washing by infusing 0.2 to 0.5ml physiological saline twice or three times, citing also Okazaki et alNyugan No Ringsho 4:587-594 (1989) (in Japanese).

[0014] A company called Diagnostics, Inc. formed in 1968, produceddevices to obtain breast ductal fluid for cytological evaluation. Thedevices included a hair-like single lumen breast duct catheter to infusefluid into a breast duct and the procedure dictated that after removalof the catheter oozing fluid was collected from the nipple surface witha capillary tube. The devices were sold prior to May 28, 1976 for thepurpose of collecting breast ductal fluid for cytological evaluation.

[0015] A lacrimal irrigating cannula is described in U.S. Pat. No.5,593,393 to inventors Trudell and Prouty. The cannula is graduated andused for insertion, dilation, probing and irrigating of the lacrimaldrainage system of the eye. Lacrimal probes have been used to accessbreast ducts as depicted in The Breast: Comprehensive Management ofBenign and Malignant Diseases (1991) vol 2, Bland & Kirby eds. W.B.Saunders Co, Philadelphia, Pa. pp. 63, FIG. 3-26.

[0016] Patents and applications that describe use of a fixed supportwire or support generally to reinforce the catheter include PCTpublication WO 97/44084, PCT publication WO 97/44082, U.S. Pat. No.5,221,255, JP 6-154334 (unexamined patent publication), U.S. Pat. No.3,792,703 to Moorehead, U.S. Pat. No. 4,596,564 to Spetzler et al, U.S.Pat. No. 5,209,734 to Hurley et al, U.S. Pat. No. 5,456,674 to Bos etal, PCT publication WO 97/31677, PCT publication WO 94/07549, PCTpublication WO 94/02197, European patent application EP 630 657 A1,European patent application EP 800 842 A1, Japanese unexamined patentpublications JP 4-226675, JP 6-277289, and JP 6-277294, Japaneseexamined patent publication JP 3-4232, and PCT publication WO 97/47230.

[0017] Patents and publications that describe use of a very smallatraumatic tip include U.S. Pat. No. 4,652,255 to Martinez, U.S. Pat.No. 5,246,430 to MacFarlane, PCT publication WO 97/37699, PCTpublication WO 97/10015, PCT publication WO 94/07549, European patentapplication EP 729 766 A1, European patent application EP 643 979 A1,Japanese examined utility model publication JP 4-4730, and Japaneseexamined patent publications JP 1-14794, JP 61-24022, and JP 61-24023.

[0018] Patents and publications that describe and claim fluid collectioncatheters having a narrow distal portion and a larger diameter proximalportion with a shoulder therebetween include PCT publication WO97/44084, PCT publication WO 97/44082, U.S. Pat. No. 5,221,255 toMahurkar, JP 2,519,873 (U.S. Pat. No. 5,470,318), U.S. Pat. No.4,553,957 to Williams et al, U.S. Pat. No. 4,652,255 to Martinez, U.S.Pat. No. 4,709,705 to Truglio, U.S. Pat. No. 5,451,208 to Goldrath, U.S.Pat. No. 5,246,430 to MacFarlane, PCT publication WO 97/48435, PCTpublication WO 97/31677, PCT publication WO 95/20983, PCT publication WO94/02197, European patent application EP 682 954 A2, European patentapplication EP 631 791 A1, Japanese examined patent publication JP4-45186, Japanese unexamined utility model publication 6-77709, PCTpublication WO 98/39046, and WO 97/47230.

[0019] Other patents or publications related in the art include thefollowing: JP 5-184664 assigned to Terumo Corp. describes a catheterwith a distal tip formed by heating; JP 2.631,320 Moriuchi et al,assigned to Terumo Corp. showing vascular catheter with multiple axialwire supports extending the length of the catheter; JP 3-264045 to Sato,assignee Terumo Corp. has a central reinforcement wire extending thelength of intravascular catheter body; JP 61-268266 (WO 89/09079) toHurley et al, assignee Sumitomo Bakelite (abandoned) depicting anotherwire reinforcement but in a uterine catheter; JP 6-502314 to Hurley etal, assignee Brigham & Women's Hospital shows a spinal catheter withspinal wire reinforcement; JP 8-112354 to Takane depicts probe withisolate lumens and distal side ports; JP 5-237191 (EP 542246) toPearsall, assignee Becton Dickinson shows rounded tips softer than thebody of the catheter; JP 3-36363 (JP 4-516C) to Kamogawa, assigneeTerumo Corp. is expired but has atraumatic tip with side ports and asingle lumen; JP 2,531,583 to Onishi, assigned to Mitsubishi shows acatheter having a soft tip formed from polymer having a glass transitiontemperature at body temperature; JP 2,681,345 to Inoue, assigneeKitasato Supply shows insemination device with syringe; JP 5-184664 toTakeoka, assignee Terumo Corp. shows a single lumen rounded tip catheterwith side ports; JP 58-46337 (JP 59-2345) to Fujimoto depicts a slidablestop on rectal catheter having side ports; and JP 58-146356 to Harrisdepicts an intrauterine catheter with shoulder stop. Patents andpublications that describe breast access for purposes other than lavageinclude U.S. Pat. No. 5,800,534 to Jeter et al.

SUMMARY OF THE INVENTION

[0020] According to the present invention, a method for obtainingcellular material from a human breast milk duct comprises introducing awash fluid to the breast milk duct, using a volume of at least 2 ml thatis present within the duct for a preselected time, and collecting atleast a portion of the introduced wash fluid from within the duct, withthe portion of wash fluid carrying the cellular material. Thepreselected time is preferably less than one second, but will usually bein the range from one second to one hour. The wash fluid is preferablyintroduced to a volume of at least 2 ml, often at least 5 ml, andtypically in the range between 5 ml and 25 ml, prior to collecting anyof the wash fluid from the duct. The wash fluid is preferably introducedto a single breast milk duct and collected from the same breast milkduct without mixing with materials from other breast milk ducts. Themethod may further comprise separating cellular material from thecollected fluid. The method may still further comprise examining theseparated cellular material. The cellular material usually includes asubstance selected from the group consisting of whole cells, cellulardebris, proteins, nucleic acids, polypeptides, glycoproteins, lipids,fats, glycoproteins, small organic molecules, metabolites, andmacromolecules.

[0021] Another aspect of the invention comprises a method for obtainingcellular material from a human breast milk duct including introducing aductal access device having at least one lumen into a duct, introducinga wash fluid through the access device lumen into the milk duct,providing a volume of at least 2 ml to be present within the duct for apreselected time, and then collecting at least a portion of the washfluid from the duct through the lumen of the access device. The methodpreferably further comprises massaging and squeezing the breast tissueafter introducing the wash fluid but prior to and/or during collecting aportion of the wash fluid. Introducing the ductal access devicetypically comprises positioning a distal end of the device distal to theductal sphincter in the breast duct. The access device preferablyincludes only a single lumen that extends into the duct. The wash fluidis preferably introduced to a volume of at least 2 ml prior tocollecting any of wash fluid from the duct. The preselected time can beless than one second, but will usually be in the range from one secondto one hour. The wash fluid can be introduced to a single breast milkduct and collected from the same breast milk duct without mixing withmaterials from other breast milk ducts. The method may still furthercomprise separating cellular material from the collected fluid. Themethod may still further comprise examining the separated cellularmaterial. The cellular material is usually a substance selected from thegroup consisting of whole cells, cellular debris, proteins, nucleicacids, polypeptides, glycoproteins, lipids, fats, glycoproteins, smallorganic molecules, metabolites, and macromolecules.

[0022] Another aspect of the invention is a method for obtainingcellular material from a human breast milk duct comprising introducing awash fluid to the breast milk duct, providing that the wash fluid ispresent within the duct for a preselected time, and collecting at leasta portion of the introduced wash fluid from within the duct, where theportion carries the cellular material; the wash fluid is introduced to asingle breast milk duct and collected from the same breast milk ductwithout mixing with materials from other breast milk ducts. The volumeof wash fluid can be at least 2 ml. The preselected time can be lessthan one second or can be in a range from one second to one hour. Themethod can further comprise separating cellular material from thecollected fluid. The method can also further comprise examining theseparated cellular material. The cellular material can be a substanceselected from the group consisting of whole cells, cellular debris,nucleic acids, lipids, protein metabolites, small organic molecules, andmacromolecules.

[0023] An aspect of the invention is another method for obtainingcellular material from a human breast milk duct comprising introducing aductal access device having at least one lumen into a duct, introducinga wash fluid through the access device lumen into the milk duct, wherethe wash fluid is present within the duct for a preselected time, andcollecting at least a portion of the wash fluid from the duct throughthe lumen of the access device; the wash fluid is introduced to a singlebreast milk duct and collected from the same breast milk duct withoutmixing with materials from other breast milk ducts. The volume of washfluid can be at least 2 ml. The preselected time can be less than onesecond or in a range from one second to one hour. The method can furthercomprise separating cellular material from the collected fluid, and theseparated material can be examined. The cellular material can be asubstance selected from the group consisting of whole cells, cellulardebris, nucleic acids, lipids, protein metabolites, small organicmolecules, and macromolecules.

[0024] An aspect of the invention is a kit comprising a ductal accessdevice; and instructions for use setting forth a method provided abovecomprising introducing a ductal access device having at least one lumeninto a duct.

[0025] An aspect of the invention is a ductal access device comprisingan access tube having a distal end, at least one lumen, and dimensionswhich permit introduction of the distal end through a ductal orifice andpositioning a distal end distal to the ductal sphincter of a humanbreast. The device can further comprise means on the access tube forpositioning the distal end distal to the ductal sphincter. Thepositioning means can comprise length indicia on the tube which permit auser to determine the depth to which the distal end of the tube has beenintroduced. The positioning means can comprise a stop element formed orattached to the tube; the stop will have dimensions which preventfurther insertion of the tube into the duct and the stop is positionedon the tube so that the distal tip will be located distal to the ductalsphincter when the device is fully inserted up to the stop. The stopelement can comprise a collar affixed to or formed on an exteriorsurface of the tube. The device can comprise means for anchoring thedevice to the breast. The device can include a receiving portioncomprising a water tight seal for receiving the dilator. The stopelement can comprise a hub attached to a proximal end of the tube, wherethe hub has a width which is greater than the diameter of the tube sothat a shoulder is formed at a junction between the tube and the hub.The positioning means can comprise a nob on the access tube having anincrease diameter for anchoring the tube in the lactiferous sinus oncethe nob has passed the sphincter and rests in the sinus. The access tubecan have an outer diameter of 0.05 inches (or 1.27 mm) or less. Theaccess tube can have an outer diameter of 0.010 inches (or 0.254 mm) orgreater. The outer diameter can be in the range from 0.010 inches (or0.254 mm) to 0.050 inches (or 1.27 mm). The access tube can have a lumendiameter 0.007 inches (or 0.178 mm) or greater. The access tube can havea lumen diameter in the range from 0.007 inches (or 0.178 mm) to 0.047inches (or 1.19 mm). The access device can further comprise an infusionconnector providing a fluid flow path into the lumen of the tube; and acollection connector providing a fluid outlet path from the lumen of thetube; the infusion and collection connectors are isolated from eachother so that the fluid may be infused through the infusion connectorand simultaneously removed through the collection connector. The devicecan further comprise a dilator removably received in the access tube andhaving a distal tip which is positionable through the access tube toextend from the distal end of the device. The dilator can have an outerdiameter of 0.024 inches (or 0.61 mm) or less. The dilator can betapered. A receiving portion of the device for receiving the dilator cancomprise a water-tight seal.

[0026] An aspect of the invention is a ductal access system comprising aductal access device as described and a container holding a premeasuredvolume of ductal wash fluid. The container can comprises a syringe forconnection to the first side port. The pre-measured volume can be in therange from 2 ml to 100 ml. The ductal access fluid is can be selectedfrom the group consisting of saline, phosphate buffered saline, anonabsorbable fluid, an isotonic solution, an osmotic solution, ahypotonic solution, and a hypertonic solution.

[0027] A further aspect of the invention is a ductal access devicecomprising an access tube having a distal end, a single lumen, anddimensions which permit introduction of the distal end through a ductalorifice and positioning a distal end of the device distal to the ductalsphincter, an infusion connector providing a fluid flow path into thelumen of the access tube, and a collection connector providing a fluidoutlet path from the lumen of the access tube; the infusion andcollection connectors being isolated from each other so that fluid maybe infused through the infusion connector and simultaneously removedthrough the collection connector. The tube has an outer diameter of0.010 inches (or 0.254 mm) or greater or the tube has an outer diameterof 0.050 inches (or 1.27 mm) or less, or the outer diameter can be inthe range from 0.010 inches (or 0.254 mm) to 0.50 inches (or 1.27 mm).

[0028] The access tube has a lumen diameter 0.007 inches (or 0.178 mm)or greater, or a lumen diameter in the range from 0.007 inches (or 0.178mm) to 0.047 inches (or 1.19 mm). The device can further comprise meanson the access tube positioning a distal end of the device distal to theductal sphincter. The positioning means can comprise length indicia onthe tube which permit a user to determine the depth to which the distalend of the tube has been introduced. The positioning means comprises astop element formed or attached to the tube, and the stop has dimensionswhich prevent further insertion of the tube into the duct; the stop ispositioned on the tube so that a distal end of the distal tip ispositioned distal to the ductal sphincter. The stop element an comprisea collar affixed to or formed on an exterior surface of the tube. Thestop element can comprise a hub attached to a proximal end of the tube,where the hub has a width which is greater than the diameter of the tubeso that a shoulder is formed at a junction between the tube and the hub.The positioning means can comprise a nob on the access tube having anincreased diameter for anchoring the distal portion of the tube distalto the sphincter once the nob has passed the sphincter. The device cancomprise means for anchoring the device to the breast. The device canadditionally comprise a dilator removably received in the access tubeand having a distal tip which is positionable through the access tube toextend from the distal end of access device. The dilator can have anouter diameter of 0.024 inches (or 0.61 mm) or less. The dilator can betapered. A receiving portion of the device for receiving the dilator ancomprise a water-tight seal.

[0029] An aspect of the invention is a ductal access system comprising aductal access device as just described and a container holding apremeasured volume of ductal wash fluid. The container can comprise asyringe for connection to the first side port. The premeasured volumecan be in the range from 2 ml to 100 ml. The ductal access fluid can beselected from the group consisting of saline, phosphate buffered saline,a nonabsorbable fluid, an isotonic solution, an osmotic solution, ahypotonic solution, and a hypertonic solution.

[0030] An aspect of the invention is a ductal access device comprising ahub having an internal elongate manifold, a lower port at a bottom ofthe manifold, and first and second side ports spaced above the lowerport; and an access tube having a distal end, a proximal end, a lumen,and dimensions which permit introduction of the distal end through aductal orifice and a positioning a distal end of the device distal tothe ductal sphincter of the human breast, provided also that theproximal end of the tube is attached to the lower port of the hub. Thefirst and second side ports can be at the same level relative to thelower port. The first side port can be below the second side port. Theaccess tube can have an outer diameter of 0.010 inches (or 0.254 mm) orgreater. The access tube can have an outer diameter of 0.50 inches (or1.27 mm) or less. The outer diameter can be in the range from 0.010inches (or 0.245 mm) to 0.50 inches (or 1.27 mm). The access tube canhave a lumen diameter 0.007 inches (0.178 mm) or greater, or a lumendiameter in a range from 0.007 inches (0.178 mm) to 0.047 inches (1.19mm). The device can have an infusion tube connected to the first port ofthe hub; and a collection tube connected to the second port of the hub.The device can further comprise a means for controlling a flow of fluidthrough the infusion tube, a means for controlling a flow of fluidthrough the collection tube, or both a means for controlling a fluidflow through the infusion lumen and a means for controlling a fluid flowthrough the collection lumen. The fluid control means can comprisecompressable lumens or the fluid control means can comprise stopcocks oneach lumen. The hub or manifold can have a volume in the range from 0.01ml to 1.0 ml. The first side port can be spaced above the lower port bya distance less than 5 mm and the second side port can be spaced abovethe first side port by a distance in the range from 0.10 mm to 5 mm. Thedevice can further comprise a dilator removably received in the hub andhaving a distal tip which is positionable through the access tube toextend from the distal end of the device. The dilator can have an outerdiameter of 0.024 inches (or 0.61 mm) or less. The dilator can bepositionable through the hub manifold and into the lumen of the accesstube. The dilator can be tapered. A receiving portion of the hub forreceiving the dilator can comprise a water-tight seal. The device canfurther comprise a means on the access tube for positioning the distalend of the access tube distal to the ductal sphincter. The positioningmeans can comprise length indicia on the tube which permit a user todetermine the depth to which the distal end of the tube has beenintroduced. The positioning means can comprise a stop element formed orattached to the tube; the stop has dimensions which prevent furtherinsertion of the tube into the duct and the stop is positioned on thetube so that the distal tip will be located distal to the ductalsphincter when the device is fully inserted up to the stop. The stopelement can comprises a collar affixed to or formed on an exteriorsurface of the tube. The stop element can comprise a hub attached to aproximal end of the tube, where the hub has a width which is greaterthan the diameter of the tube so that a shoulder is formed at a junctionbetween the tube and the hub. The device can further comprise a meansfor anchoring the device to the breast. The positioning means cancomprise a nob on the access tube having an increased diameter foranchoring the tube distal to the ductal sphincter once the nob haspassed the sphincter and rests distal to it.

[0031] An aspect of the invention is a ductal access system comprising aductal access device as just described and a container holding apremeasured volume of ductal wash fluid. The container can comprise asyringe for connection to the first side port. The pre-measured volumecan be in the range from 2 ml to 100 ml. The ductal access fluid can beselected from the group consisting of saline, phosphate buffered saline,a nonabsorbable fluid, an isotonic solution, an osmotic solution, ahypotonic solution, and a hypertonic solution.

[0032] An aspect of the invention provides a ductal access cathetercomprising a catheter body having a distal end and a proximal end andincluding at least a distal portion and a proximal portion wherein thedistal portion has a cross-sectional geometry which can be insertedthrough a ductal orifice into a ductal lumen of a human breast; whereinthe proximal portion has a cross-sectional geometry which inhibitsinsertion through the ductal orifice and into the ductal lumen; andwherein the catheter body has at least an infusion lumen and ancollection lumen each of which has a distal port near a distal end ofthe distal portion and a proximal connector near a proximal end of theproximal portion. The device can further comprise a means forcontrolling a flow of fluid through the infusion lumen, a means forcontrolling a flow of fluid through the collection lumen, or both ameans for controlling a fluid flow through the infusion lumen and ameans for controlling a fluid flow through the collection lumen. Thefluid control means can comprise compressable lumens, or the fluidcontrol means can comprise stopcocks on each lumen.

[0033] The distal portion of the catheter body can be stiffened over atleast a part of its length to facilitate insertion through the ductalorifice and into the ductal lumen. The stiffened distal portion of thecatheter body has an average bending stiffness in the range from about0.010 inch-lbs to about 0.5 inch-lbs. The stiffening member is disposedin the distal portion of the catheter body.

[0034] The distal portion of the catheter body has a maximum width inthe range from 0.016 inches to 0.022 inches (0.56 mm) and the proximalportion of the catheter body has a minimum width in the range from 0.023inches (0.58 mm) to 0.028 inches (0.71 mm). The distal portion of thecatheter body has a generally tubular structure with a diameter in therange from 0.010 inches (0.254 mm) to 0.020 inches (0.51 mm) and theproximal portion of the catheter body has a generally tubular structurewith a diameter in the range from 0.030 inches (0.762 mm) to 0.10 inches(0.254 mm) and wherein the proximal diameter is greater than the distaldiameter by at least 0.010 inches (or 0.254 mm). At least one of thedistal collection port and the distal infusion portion can be disposedon a side of the distal portion of the catheter body. The distalcollection port and the distal infusion port can both be located on theside of the distal portion of the catheter body. The distal collectionport and the distal infusion port can be axially aligned. The distalcollection port and the distal infusion port can be axially spacedapart. The catheter body can include an atraumatic distal tip. The tipcan be composed of a soft polymeric material, have a diameter in therange from about 0.008 inches (0.20 mm) to about 0.035 inches (0.89 mm),and a length in the range from about 0.25 cm to about to 2.5 cm.

[0035] The invention further provides a ductal access cathetercomprising a catheter body having a distal end and a proximal end andincluding at least a distal portion and a proximal portion; wherein thedistal portion has a cross-sectional geometry which can be insertedthrough a ductal orifice into a ductal lumen of a human breast; whereinthe distal portion of the catheter body is stiffened over at least apart of its length to facilitate insertion through the ductal orificeand into the ductal lumen; and wherein the catheter body has at least aninfusion lumen and an collection lumen each of which has a distal portnear a distal end of the distal portion and a proximal connector near aproximal end of the proximal connector. The stiffened distal portion ofthe catheter body can have an average bending stiffness in the rangefrom about 0.010 inch-lbs to about 0.5 inch-lbs. The proximal portioncan have a cross-sectional geometry that inhibits insertion through theductal orifice and into the ductal lumen.

[0036] The invention also provides a ductal access catheter comprising acatheter body having a distal end and a proximal end and including atleast a distal portion and a proximal portion; wherein the distalportion has a cross-sectional geometry which can be inserted through aductal orifice into a ductal lumen of a human breast; and wherein thecatheter body has at least an infusion lumen and an collection lumeneach of which has a distal port near a distal end of the distal portionand a proximal connector near a proximal end of the proximal connector;and wherein the distal collection port and the distal infusion port areboth located on the side of the distal portion of the catheter body. Thedistal collection port and the distal infusion port can be axiallyaligned. The distal collection port and the distal infusion port can beaxially spaced apart. The proximal portion can have a cross-sectionalgeometry that inhibits insertion through the ductal orifice and into theductal lumen.

[0037] Another aspect of the invention is a method for lavage of aductal network in a human breast comprising providing a multi-lumencatheter as just described and inserting the distal portion of thecatheter through a ductal orifice and into a distal lumen of the ductalnetwork; introducing a wash fluid through the infusion lumen into theductal network; and withdrawing the wash fluid and substances borne bythe wash fluid from the ductal network through the collection lumen.

[0038] Another aspect of the invention is a system comprising amulti-lumen catheter as just described and instructions for use settingforth a method for lavage of a ductal network in a human breastincluding introducing a wash fluid through the infusion lumen into theductal network and withdrawing the wash fluid and substances borne bythe wash fluid from the ductal network through the collection lumen.

[0039] The agent infused into the duct can comprise a non-absorbablefluid and/or an oncotic agent and/or an osmotic agent. The agent can besoluble. The agent can comprise a molecule that is a protein, a colloid,a sugar, or a polymer. The agent can be mannitol, sorbitol, glucose,glycerol, sucrose, raffinose, fructose, lactulose, sodium chloride,polyethyleneglycol (PEG), maltodextrin, dextran (e.g. dextran 70),hydroxyethyl starch, fluid gelatin, or a synthetic colloid. The agentcan comprise a protein and the protein can be a binding protein or anantibody. The binding protein can be albumin. Administering can compriseadministering locally, and local administration can compriseadministering intraductally. A system for increasing or standardizing anamount of fluid collectable from a milk duct of a breast can compriseinfusing a nonabsorbable fluid and/or an osmotic agent and/or an oncoticagent into the ductal lumen, a medical tool for delivering the agent tothe ductal lumen, and instructions for use.

BRIEF DESCRIPTION OF THE DRAWINGS

[0040]FIG. 1 shows a single lumen catheter with a stop and externalinfusion and collection tubes.

[0041]FIG. 2 is a detailed view of a calibrated ductal access portion ofa single lumen catheter. The calibration serves to identify a depth ofpenetration.

[0042]FIG. 3 is a single lumen ductal access catheter having a hub andinfusion and collection lumens and a retractable dilator.

[0043]FIG. 3A is a cross section of the device in FIG. 3.

[0044]FIG. 4A illustrates access of a breast duct and penetration to atleast a region distal to the ductal sphincter.

[0045]FIG. 4B illustrates filling a duct with infusion fluid.

[0046]FIG. 4C illustrates bidirectional flow of infused fluid in theduct through the access lumen to be collected.

[0047]FIG. 4D illustrates a single lumen catheter accessing a breastduct having the capacity to infuse and collect fluid outside theaccessed breast duct.

[0048]FIG. 5 depicts a kit comprising a single lumen catheter havinginfusion and collection lumens outside the ductal access portion of thecatheter, a premeasured solution to infuse into the duct andinstructions for use of the catheter and wash fluid to access a breastduct and retrieve cellular material.

[0049]FIG. 6 depicts a single or double lumen catheter having aninfusion and collection lumen outside the catheter with stopcocks oneach external lumen to control fluid flow into or out of each lumen.

[0050]FIG. 7 illustrates a breast duct accessed by a single or doublelumen catheter having separate infusion and collection lumens outsidethe ductal access portion of the catheter, having also stop cocks oneach external lumen for controlling fluid flow in the lumen, and havingan infusion receptacle on the infusion lumen and a collection receptacleon the collection lumen.

[0051]FIG. 8 illustrates an alternative embodiment of the breast ductaccess device of the present invention.

[0052]FIGS. 8A and 8B are cross sectional views taken along lines 8A-8Aand 8B-8B of FIG. 8, respectively.

[0053]FIG. 8C is a detailed view of the distal end of the device of FIG.8.

[0054]FIGS. 9A and 9B depict alternative transition zones in a ductalaccess catheter. FIG. 9A is a stepped transition zone.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS OF THE INVENTION

[0055] The following preferred embodiments and examples are offered byway of illustration and not by way of limitation.

[0056] The invention provides methods for obtaining cellular materialfrom a human breast duct. A wash fluid is introduced and a volume of atleast 2 ml is allowed to remain in the duct for a preselected time thatcan range from less than or about one second to about an hour, includingany length of time in between. During the time that the wash fluidremains in the breast duct, it may mix with the ductal fluid alreadypresent in the duct, and it may accumulate cellular material either fromthe ductal lumen walls or that already present in the existing residentductal fluid. The breast duct may be filled with wash fluid before thewash fluid mixed with ductal fluid and comprising cellular material iscollected. For example, a wash fluid may be infused into the duct untila point of resistance to infusion, a which point it may be consideredthat the breast duct may is filled with wash fluid, and the just infusedfluid can be allowed to reside in the duct for a preselected time. Oncethe time has elapsed, the infused fluid and the contents of the ductwith which it has mixed is collected. If a ductal access tool is used toaccess the duct and infuse the fluid into the duct, the in-dwelling toolcan obtain or collect the infused fluid either through the same lumenthat was used to infuse the wash fluid into the duct originally, orthrough a separate second lumen adjacent or coaxial to the infusionlumen. In any event the access tool remains in place in the duct duringthe infusion, filing, preselected waiting time (e.g. less than onesecond or about one second to one hour), and collection of the washfluid mixed with ductal fluid and cellular material from the breastduct.

[0057] Methods of the invention include accessing a single breast ductand obtaining cellular material from that duct without allowing thecellular material or ductal fluid from the accessed duct to contact thecellular material or ductal fluid of any other duct, or cellularmaterial or ductal fluid that happens to be residing on the nipplesurface. Thus is provided the opportunity to analyze a single individualbreast duct separate from other breast ducts of the patient. The washfluid can be introduced into the duct by accessing the breast duct witha ductal access device having at least one lumen. Infusion of wash fluidinto the duct is provided through the lumen accessing the duct.Collection of the wash fluid mixed with ductal fluid and comprisingcellular material can also be provided through the lumen accessing theduct. Access of a single breast duct provides also the opportunity tocollect ductal fluid and cellular material from the accessed breast ductseparate from other breast ducts on the breast, without mixing orcontacting the collected fluids and cellular material with that of theother ducts, and so providing the opportunity to analyze the conditionof the accessed duct separately.

[0058] During the procedure the breast may be massaged and squeezed.Massaging and squeezing the breast may facilitate collection of theinfused fluid and mixed ductal fluid and cellular material. The actionsof massaging and squeezing the breast may also provide some disruptionof the cells on the lumen walls, thereby increasing a yield of cellularmaterial from the procedure. Collection from a collection lumen (eitherthe same lumen as was used to infuse or a separate lumen) can be furtherfacilitated in some cases with aspiration applied into the lumen.Preferably, where an indwelling tool is used, a single lumen accessesthe breast duct, and external to the breast and breast duct the toolbranches into an infusion lumen and a collection lumen. From thiscollection lumen, during the period when the fluid is being collectedfrom the duct, aspiration may be applied.

[0059] Additionally, where a manifold hub is present in the design ofthe access tool, once the wash fluid mixed with ductal fluid andcellular material is passed out of the duct and into the hub, collectionmay be facilitated from the collection lumen without risk of collapsingthe ductal wall, but providing an aspiration pressure in the collectionlumen (e.g. using a syringe and pulling back to collect material intothe syringe). Additionally, or alternatively, the hub filled withcollected material may be flushed into the collection lumen using aninfusion of wash fluid from the infusion lumen. The fluid flow into andout of the infusion and collection lumens may be facilitated with meanson the device lumens to stop or open the fluid flow into or out of thelumens.

[0060] Additionally, when a ductal access device is used to access abreast duct, the distal end of the device comprising an infusion and/orcollection port or ports is placed distal to the ductal sphincter toprovide an optimal position for infusion and collection of fluid and/orother agents or materials to and from the breast duct. Means to assureplacement of the distal tip of the device distal to the ductal sphinctercan be provided on the device as further discussed below in the ductalaccess device design.

[0061] The wash fluid that is introduced into the duct can comprise anybiocompatable agent or solution. Thus, the wash fluid can comprise e.g.saline, phosphate buffered saline. Additionally or alternatively, thewash fluid can comprise an agent or agents or solution that reduces theability of the fluid or agent to diffuse through the ductal wall orotherwise leave the duct and enter other parts of the body. Accordingly,the wash fluid may comprise a nonabsorbable fluid, an isotonic solution,an osmotic solution, a hypotonic solution or a hypertonic solution.Fluid or agents may be administered to the breast duct in order tofacilitate, increase, and/or optimize the amount of material obtained orobtainable from the breast duct during the procedure. Agents orsolutions that may comprise the infused wash fluid can include, e.g.protein, colloid, sugar, polymer, mannitol, sorbitol, glucose, glycerol,sucrose, raffinose, fructose, lactulose, sodium chloride,polyethyleneglycol (PEG), maltodextrin, dextran (e.g. dextran 70),hydroxyethyl starch, fluid gelatin, albumin, a synthetic colloid, anantibody or part of an antibody, or a binding protein.

[0062] Once the wash fluid had been infused in the duct and the washfluid and ductal fluid is collected from a breast duct, the cellularmaterial can be separated and can be examined. The cellular material caninclude, e.g. substances selected from the group consisting of wholecells, cellular debris, proteins, nucleic acids, polypeptides,glycoproteins, lipids, fats, glycoproteins, small organic molecules,metabolites, and macromolecules. Whole cells can be examined bycytology, or any other suitable method for analyzing the condition ofthe cells. Other markers present in the cellular material, ductal fluidgenerally, or other material obtained from the breast duct can beanalyzed as is appropriate for the marker being sought, including e.g.binding assays, immunohistochemistry, or using other analyticaltechnology for distinguishing and identifying biological moleculesobtained from biological material.

[0063] Chromosomal abnormalities in ductal epithelial cells can alsoprovide information and act as a marker to identify cancer or precanceras described in Mark et al (1999) Cancer Genet Cytogenet 108:26-31;Lundlin and Mertens (1998) Breast Cancer Res Treat 51:1-15; Newsham(1998) Am J Pathol 153:5-9; Larson et al (1998) Am J Pathol 152:1591-8;Adelaide et al (1998) Genes Chromosomes Cancer 22:186-99; Fejzo et al(1998) Gene Chromosome Cancer 22:105-113; Dietrich et al (1998) HumPathol 12: 1379-82; Cavalli et al (1997) Hereditas 126:261-8; Adeyinkaet al (1997) Cancer Genet Cytogenet 97:119-21; Afify and Mark (1997)Cancer Genet Cytogenet 97:101-5; Brenner and Aldaz (1997) Prog Clin BiolRes 396: 63-82; Mark et al (1997) Ann Clin Lab Sci 27:47-56; and Fabianet al 1993 J. Cellular Biochemistry 17G:153-16.

[0064] In addition, exemplary markers are described in Masood S.,(Prediction of recurrence for advanced breast cancer. Traditional andcontemporary pathologic and molecular markers) Surgical Oncology Clinicsof North America. 4(4):601-32, 1995; Lopez-Guerrero et al (1999) JHematother 8(1):53-61; Marjumdar and Diamandis (1999) Br J Cancer79(9-10):1594-602; Balleine et al (1999) Br J Cancer 79 (9-10):1564-71;Houston et al (1999) Br J Cancer 79(7-8):1220-6; Nikolic-Vukosavljevicet al (1998) Tumori 84(6):691-4; Maguire et al (1998) Int J Biol Markers13(3):139-44; Stearns et al (1998) Breast Cancer Res Treat52(1-3):239-59; Eiriksdottir et al (1998) Eur J Cancer 34(13):2076-81,and U.S. Pat. No. 5,169,774. Many known breast cancer markers arediscussed and described in readily available medical text books onbreast cancer. In addition, several markers can be identified andanalyzed in the same sample, e.g. Fabian et al 1993 J. CellularBiochemistry 17G: 153-16 and Fabian et al 1994 Breast Cancer Res Treat30(3):263-74 looking at estrogen receptor (ER), epidermal growth factorreceptor (EGFR), mutant p53, HER-2 neu by immunohistochemistry andaneuploidy by image analysis in fine needle aspirates.

[0065] Cytological assays that can be performed on the cells retrievedfrom a duct or from nipple aspirate can include e.g. assays described inKing et al, J. Nat'l Cancer Inst (1983) 71:1115-21, Wrensch et al.(1992) Am. J. Epidem. 135: 130-141, Papanicolaou et al, (1958) Cancer,11:377-409 and Goodson W H & King E B, Chapter 4: Discharges andSecretions of the Nipple, THE BREAST: COMPREHENSIVE MANAGEMENT OF BENIGNAND MALIGNANT DISEASES (1998) 2^(nd) Ed. vol 2, Bland & Kirby eds. W.B.Saunders Co, Philadelphia, Pa. pp. 51-74. For example, as described inGoodson and King (page 60) atypical hyperplasia presents as havingcellular abnormalities, increased coarseness of the chromatin, andtendency for more single cells as well as groups of cells. With regardto carcinoma in situ, Papanicolaou et al, described cellularabnormalities, e.g. nuclear abnormalities diagnosed by cytology of fluidfrom nipple secretions containing ductal cells. The cytology of abnormalcells can also be conducted as described in Sartorius et al (1977) J.Natl Cancer Inst 59: 1073-1080. and King et al, (1983) JNCI71(6)1115-1121. Atypia and carcinoma in situ are widely characterizedpathologically, as described in Page et al, (1998) Mod Pathol 11(2):120-8. The ductal fluid can be analyzed by cytological techniques byplacing some of the fluid on a slide with a standard cytological stainusing a light microscope. The cells can be studied for atypical growthpatterns in individual cells and clusters of cells using publishedmethods, including Mouriquand J, (1993) S Karger Pub, “Diagnosis ofNon-Palpable Breast Lesions: Ultrasonographically Controlled Fine-NeedleAspiration: Diagnostic and Prognostic Implications of Cytology” (ISBN3805557477); Kline T S and I K, Pub Igaku-Shoin Medical ““Breast: Guidesto Clinical Aspiration Biopsy” (LSBN 0896401596; Masood, AmericanSociety of Clinical Pathology: November 199S, “Cytopathology of theBreast” ISBN 0891893806; and Feldman P S, American Society of ClinicalPathology, November 1984,“Fine Needle Aspiration Cytology and ItsClinical Applications: Breast and Lung” ISBN 0891891846.

[0066] Other references that discuss cytological analysis and which giveguidance to an analysis of ductal epithelial cells derived from ductalfluid include Silverman et al, (Can FNA biopsy separate atypicalhyperplasia, carcinoma in situ, and invasive carcinoma of the breast?:Cytomorphologic criteria and limitations in diagnosis, DiagnosticCytopathology) 9(6):713-28, 1993; Masood et al, (Immunohistochemicaldifferentiation of atypical hyperplasia vs. carcinoma in situ of thebreast) Cancer Detection & Prevention. 16(4):225-35, 1992; Masood et al,(Cytologic differentiation between proliferative and nonproliferativebreast disease in mammographically guided fine-needle aspirates)Diagnostic Cytopathology.7(6):581-90, 1991; Masood S., (Occult breastlesions and aspiration biopsy: a new challenge) DiagnosticCytopathology. 9(6):613-4, 1993; Masood S., (Prognostic factors inbreast cancer: use of cytologic preparations) Diagnostic Cytopathology.13(5):388-95, 1995; Novak and Masood, (Nuclear grooves in fine-needleaspiration biopsies of breast lesions: do they have any significance?)Diagnostic Cytopathology. 18(5):333-7, 1998; Sidawy et al,(Interobserver variability in the classification of proliferative breastlesions by fine-needle aspiration: results of the Papanicolaou Societyof Cytopathology Study) Diagnostic Cytopathology. 18(2):150-65, 1998;Masood et al, (Automation in cytology: a survey conducted by the NewTechnology Task Force, Papanicolaou Society of Cytopathology) DiagnosticCytopathology. 18(l):47-55, 1998; and Frykberg and Masood Copeland E M3d. Bland K I., (Ductal carcinoma in situ of the breast) Surgery,Gynecology & Obstetrics 177(4):425-40, 1993.

[0067] Appropriate animal models for breast cancer therapies have beendescribed, e.g. McKenzie and Sukumar, (Molecular mechanisms of chemicalcarcinogenesis in rodent models) Cancer Treatment & Research 71:313-29,1994; Chen et al, (Midkine in the progression of ratN-nitroso-N-methylurea-induced mammary tumors) Molecular Carcinogenesis.17(3):112-6, 1996; and Sukumar et al, (Animal models for breast cancer)Mutation Research 333(1-2):37-44, 1995.

[0068] In addition to some markers discussed and/or articles or bookscited on breast cancer and breast precancer markers, the followingcancer markers are listed here as exemplary and may be used as well asother markers to analyze the condition of a breast duct. Standard assayprocedures for identifying the markers can be used, including antibodiesor other binding partners, labels, stains, pattern analysis (for cellsand cell components), and in general any other chemical or visualidentification techniques. The following are exemplary potential markersfor such identification and analysis: cathepsins (including cathepsinD); maspin, fas, fas ligand, tissue inhibitor of matrixmetalloproteinas-1 (TIMP-1); chemokines (both C-C and C-X-C typechemokines); collagenases, metalloproteinases, TIMP's, cathepsins,disrupted basement membrane epitopes, stromolysin-3; cytokeratins (e.g.keratin 14, B1, KA1, KA4 and 312C8-1); estrogen and progesteronereceptors (or any androgen or other steroid receptor); growth factorreceptors for members of the fibroblast growth family (FGF) includingFGF1-18, vascular endothelial growth factor (VEGF), insulin-like growthfactor-1 (IGF-I), IGF-II, platelet-derived growth factor (PDGF),keratinocyte growth factor (KGF), and epithelial growth factor (EGF);placental growth factor (PLGF), hepatocyte growth factor (HGF), tumornecrosis factor (TNF), transforming growth factor (TGF) both alpha andbeta forms, and angiopoietin, for example; growth factors and cytokinesincluding e.g. FGF1-18, VEGF, IGF-I, IGF-II, PDGF, KGF, EGF, PLGF, HGF,TNF, TGF alpha and beta, angiopoietin; heat shock proteins (HSP) (e.g.HSP27) 27 (HSP27); ErB type 1 tyrosine kinase receptors (e.g. Her2 (anEGF receptor) or any ligand or receptor of the ErbB family of ligandsand receptors); integrins, selecting, cadherins, for example (i.e. alphaand beta 3 integrin); keratin-14; known cancer antigens including, forexample Ki-67, Ki-S1, p53, nm23, bcl-2, p21 ras, cyclins, and pS2;thrombin receptor activating peptide; urokinase, urokinase-typeplasminogen activator (UPA), plasmin antiplasmin; UPA receptor (UPAR),fibrinogen, plasmin activator inhibitor-I and 2 (PAI-1 and 2);telomerase; antibodies to tumor associated antigen-72 (TAG-72) (e.g.B72.3, B6.2, and TKH2); carcinoembryonic antigen (CEA) (see e.g. EP319,686); prostate specific antigen (PSA); gross cystic disease fluidprotein-15 (GCDFP-15); lactose dehydrogenase (LDH); chromosomalabnormalities (e.g. aneuploidy or other abnormalities); S 1 protein;alkaline phosphatase; myosin; sialyl Tn (STn) glycopeptide (e.g.TAG-72); Tn glycopeptide; and nuclear matrix proteins (as described inprovisional patent application filed 11-17-99 docket no. PDH 99-029,herein incorporated by reference in its entirety).

[0069] In general, markers can be categorized nonexclusively, and oftenin overlapping categories as follows: 1. Markers that are detected ordetectable by virtue of protein expression or overexpression (detectionmay occur, e.g. by immunohistochemistry or in situ hybridization); 2.Markers that are detected or detectable by virtue of mRNA expression oroverexpression (detection may occur, e.g. by differential displaytechniques); 3. Markers that are detected or detectable by virtue of apost translational change in a protein, e.g. a phosphorylation of theprotein, a ubiquitination, a farnesylation, methylation, or othermodification to the protein that can be detected, e.g. by antibodiesspecific to the post translational modification.

[0070] Accordingly, markers such as the following can sought in ductalfluid, e.g. proteins that are overexpressed, mRNA transcripts that areover expressed, and proteins comprising post translationalmodifications. For example, the following markers can be identified todistinguish a cancer or precancer cell from a normal cell. Proteins thatare overexpressed can include e.g. Stromelysin-3, Membrane Type 1 MatrixMetalloproteinase (MT1-MMP), Matrix Metalloproteinase-3 (MMP-3),Placental Isoferrintin (p43), Nuclear Matrix Protein (NMP22), NM-200.4specific antigen, Vascular Endothelial Growth Factor (VEGF), Endoglin(CD105), Telomerase, ErbB-2, ErbB-3, Carcinoembryonic Antigen (CEA),Heat Shock protein-27 (HSP-27), Breast Cancer-specific Gene (BCSG),Plasminogen Activator Inhibitor (PAI-1), Urokinase PlasminogeneActivator (uPA), Urokinase Plasminogene Activator Receptor (uPAR),Colony Stimulating Factor-1 (CSF-1), Colony Stimulating Factor-1receptor (fins), Annexin I, Vasopressin, the CC Chemokine Regulated onActivation Normal T cell Expressed and Secreted (RANTES), 44-3A6specific antigen, A-80 specific antigen, MUC-1, H23 specific antigen, 83D4 specific antigen, SP-2 specific antigen, 3231A3 specific antigen,tumor associated antigen-72 (TAG-72), and MBE6 specific antigen.

[0071] Other breast cancer markers detected by any means including e.g.protein expression, mRNA expression, or post translational modificationcan include e.g. (listed alphabetically) alanine aminopeptidase, alpha 6integrin, alpha-lactalbumin, AN43, p53, Bcl2-antagonist of cell death(Bad), Bcl2-associated athanogene (BAG-1), Bcl2-antagonist/killer I(Bak), Bcl2-associated X protein (Bax), Breast cancer antigen 225(BCA225), B-cell CLL/lymphoma 2 (Bcl-2), Bcl2-like 1 (Bcl-x), beta 1-6branched oligosaccharides, beta-2 microglobulin (BMG), Bcl2 relatedprotein A1 (Bfl-1), bone sialoprotein (BSP), CCAAT/enhancer-bindingprotein liver-enriched inhibitory protein (C/EBPbeta-LIP), CarcinomaAntigen 1 (Ca 1), Carcinoma Antigen 27.29 (CA 27.29), Carcinoma AntigenM26 (CA M26), Carcinoma Antigen M29 (CA M29), Carcinoma Antigen 125(CA125), Carcinoma Antigen 15.3 (CA15.3), Carcinoma Antigen 195 (CA195),Carcinoma Antigen 19-9 (CA19-9), Carcinoma Antigen 50 (CA50), CarcinomaAntigen 549 (CA549), Cadherin-11, calcitonin receptor (CTR), cathepsinB, cathepsin L, Endoglin (CD105), CD24, CD34 (pan-endothelial marker),CD44, c-met/hepatocyte growth factor receptor, c-myc, cyclooxygenase-1(Cox-1), cyclooxygenase-2 (Cox-2), caspase-3 (CPP32), Cyclic nucleotidephosphodiesterase, cycline E, DNA topoisomerase II-alpha, DNAtopoisomerase II-beta, EGF, EGF receptor, E-selectin, fasthomoarginine-sensitive alkaline phosphatase (FHAP), fatty acid synthase,ferritin, gross cystic disease fluid protein (GCDFP-15/BRST-2),metastasis-associated h-mts1 (S100A4), heat shock cognate protein-73(hsc73), heat shock protein-70 (hsp70), heat shock protein-90 alpha(hsp90alpha), heat shock protein-90 beta (hsp90beta), inhibitors ofdifferentiation-1 (ID1), inhibitors of differentiation-3 (ID3),interleukin-1 beta, Keratin 8, Keratin 18, Keratin 19, Laminin, Lamininreceptor (MLuC5), Leucine Aminopeptidase (LAP), lipid-bound sialic acid(LSA), Melanoma antigen-1 (MAGE-1), Melanoma antigen-2 (MAGE-2),Melanoma antigen-3 (MAGE-3), Man6-P glycoproteins, Mucin-like carcinomaassociated antigen (MCA), myeloid cell leukemia-1 (Mcl-1),metallothionein (MT), mitogen-activated protein kinase phosphatase-1(MKP-1), Matrix Metalloproteinase-2 (MMP-2), Matrix Metalloproteinase-9(MMP-9), mammary serum antigen (MSA), breast cancer mucin-2 (MUC-2),breast cancer mucin-3 (MUC-3), breast cancer mucin-6 (MUC-6), Nm23nucleoside diphosphate kinase, omithine decarboxylase (ODC), osteopontin(OPN), P114 (MAR binding protein), P120 (a nucleolar proliferationantigen), focal adhesion kinase p125FAK, nuclear autoantigenp330d/CENP-F, plasminogen activator inhibitor-2 (PAI-2), Pepsinogen C,placental alkaline phosphatase (PLAP), Platelet factor 4 (angiogenicmarker), protein kinase C (PKC), prostate specific antigen (PSA),pyrimidine nucleoside phosphorylase, ras p21, reduced glutathione (GSH),retinoid X receptor alpha, ribosomal S2 protein, sialyltransferase,Stromelysin-1 (MMP-3), surfactant proteins A, surfactant proteins B,tumor associated antigen-12 (TAG-12), trefoil gene TFF1, trefoil geneTFF3/ITF/hP1.B, Thrombin, Thrombomodulin, thymidine phosphorylase (TP),thymosin beta 15, tissue cytosol ferritins, tissue polypeptide antigen(TPA), tissue polypeptide specific antigen (TPS), Vascular EndothelialGrowth Factor-B (VEGF-B), Vascular Endothelial Growth Factor-C (VEGF-C),Vascular Endothelial Growth Factor receptor-1(VEGFR1), VascularEndothelial Growth Factor receptor-2 (VEGFR2), and Vascular EndothelialGrowth Factor receptor-3 (VEGFR3).

[0072] Some Genes are overexpressed and can be found by differentialdisplay, including e.g. Claudin-7, Zinc-alpha-2-glycoprotein,Apolipoprotein B, B94, EST (R08988), Thrombospondin (THBS1), FGF-1,NGAL/Lipocalin 2, EST (N77731), BS247 [Abbott Labs WO 9922027], AIB-1.Post translational modifications can be identified in proteins,including e.g. Tyrosine phosphorylation, ErbB-2, and EGFR. Absence ofkey tumor suppression markers include e.g. mammastatin and maspin.

[0073] Turning now to the figures, FIG. 1 provides a ductal accessdevice comprising 10 an access tube 12 having a distal end 14, at leastone lumen therethrough, and dimensions which permit introduction of thedistal end through the ductal orifice and positioning a distal endthereof distal to the ductal sphincter of a human breast, e.g.,typically having an outer access tube diameter in the range from 0.5 mmto 1 mm, preferably being tapered within this range over a length from 2to 3 mm. The device can also comprise means on the access tool forpositioning the distal end distal to the ductal sphincter. The devicecan have a stop 16 or other means to prevent the device from penetratingthe duct too deeply. Alternatively, the tube could have a shoulder orother enlargement to block penetration at a point at which it isdesirable to stop the penetration of the tool; or, alternatively, acollar can be placed or built onto the external portion of the accesstube to prevent penetration beyond the collar.

[0074] The means provided to position the device distal to the ductalsphincter can comprise marks 18 on the access portion of the device toindicate a penetration depth as indicated in FIG. 2. Additionally, itmay be desired that the device is anchored just distal to the ductalsphincter once the distal tip has passed through the ductal sphincter.This may be facilated by any number of means, including, e.g. placing asmall nob or hub 20 on the tube 12 which acts a stop to resist removingthe distal tip once the nob has passed by the ductal sphincter andresides distal to it. Anchoring the distal tip of the ductal accessdevice distal to the ductal sphincter may also be accomplished byplacing the distal tip to a depth beyond the ductal sphincter andinflating a balloon (not shown) to anchor the device below the ductalsphincter during the infusion and collection procedure.

[0075] The device may also comprise a stop or hub or other means forkeeping the tube accessing the duct from penetrating too far, and forpositioning the access tube distal to the ductal sphincter. Thus, thedevice may include a positioning means comprising a stop element formedor attached to the tube. The stop element has dimensions which preventfurther insertion of the tube into the duct, and the stop is positionedon the tube so that the distal tip will be located distal to the ductalsphincter when the device is fully inserted up to the stop, thusensuring correct positioning of the tube in the duct relative to theductal sphincter. The access lumen will terminate in at least one portfor fluid infusion and/or collection, and the port is preferably placedat the end of the distal tip of the device so that it opens in a distal(axial) direction relative to the access tube 12, and the port ispreferably located relative to the stop element so that the port residesdistal to the ductal sphincter when the stop element engages the nipple.The stop element can comprise a hub attached to a proximal end of thetube, wherein the hub has a width which is greater than the diameter ofthe tube so that a shoulder is formed at a junction between the tube andthe hub.

[0076] The access device can also be anchored to the external portionsof the accessed breast by any means capable of accomplishing theanchoring. During the procedure it is important that the access devicenot slip out of the duct. Portions of the device that are external tothe access breast duct can be affixed, strapped, tethered, taped, orotherwise anchored to the breast during the procedure in order to ensurethat the device does not slip out of the duct. Such anchoring alsoprovides the practitioner with better control of the device parts ifpart or all of the device is anchored, and therefore does not need to beheld by the practitioner or an assistant.

[0077] In a preferred aspect of the catheter design, the access tube 12will branch into an infusion arm 22 and collection arm 24. The infusionarm 22 terminates in a connector 26 which removably connects to asyringe 28 or other pressurized source of wash fluid. The collection arm24 will preferably include a valve 30 and an end connector 32 forremovable attachment to a collection apparatus, such as a vial, tube,tray, microliter plate, another syringe, or the like. As discussedbelow, the collection arm will usually be closed, e.g., with valve 30,during infusion of the wash fluid. Preferably, both the infusion armlumen and collection arm lumen will be connected to a single lumenwithin the access tube 12.

[0078] Turning now to FIG. 3, a preferred embodiment of the device isshown in a single lumen ductal access device 30 having a tube 32 thataccesses the duct and through which fluid is infused, and from whichfluid is collected or drawn up out of the duct. A hub 34 is connected toan infusion tube 36 from which fluid is infused into the access tube 32and a collection tube 38 from which fluid is collected from the accesstube. The collection tube 38 is preferably attached to the hub 34 at aposition no closer to the access tube 32 than the infusion tube 36.Preferably, the collection tube 38 is located further away from theaccess tube 32 than is the infusion tube 36. A stylet 40 is optionallyprovided to facilitate introduction of the access tube through a ductalorifice into a ductal lumen. The stylet 40 will pass through apneumostatic seal at a proximal end 42 of the hub 34 so that the styletcan be removed after positioning of the access tube 32 and prior to theinfusion/collection of the wash fluid.

[0079] Fluid is infused into the hub 34 and into the duct untilresistance is met during the infusion. At this time, it is assumed thatthe duct is filled. The infusion lumen can be closed and the fluidallowed to remain in the duct for a preselected time. During thispreselected time, the breast may be massaged and squeezed to stimulatemixing of the wash fluid and ductal fluid, and also ultimately toencourage the fluid to leave the duct and enter the manifold hub. Thecollection lumen is opened and the breast squeezed to urge the fluid toprogress through the access tube in the hub. If desired, when cloudyreturn fluid is seen in the hub (which is preferably transparent orincludes a transparent window), the infusion lumen can be opened andfluid infused to push the fluid that has collected in the hub into thecollection lumen and a waiting collection receptacle. Alternatively, andpossibly additionally, aspiration pressure can be applied at thecollection lumen to aspirate any fluid remaining in the hub into thecollection receptacle. The process is repeated either following anotherinfusion of fluid into the duct or by another round of squeezing toencourage return and collection of the infused fluid.

[0080] The stylet 40 can be made of metal or hard plastic and may have atapered and/or an atraumatic tip for gently probing and accessing abreast duct. Preferably, a tapered tip 44 will extend distally of theaccess tube 32 as the tube is introduced. After access of the duct iscomplete, the stylet 40 can be withdrawn and the access tube positionedso that its distal end is distal to the ductal sphincter. The dilatorreceiving portion at the proximal end of the device can be a water tightmembrane or sheath to provide a sterile environment in the hub even withpenetration and withdrawal of the dilator, and to provide an appropriateamount of resistance so that the probe can be manipulated into the outof the duct and the access tube. The dilator stated in FIG. 3 isremovably received in the access tube and has a distal tip which ispositionable through the access tube to extend from the distal end ofthe access tube. In addition to providing tapered access, the stylet 40selectively stiffens the access tube to further ease introduction intoand through the ductal orifice. The access tube 32 may have an outerdiameter in a range from about 0.25 mm to 1.25 mm with an inner lumendiameter in the range from 0.2 mm to 1.2 mm.

[0081] As illustrated in FIG. 3A, the hub 34 can have an infusionconnector 46 providing a fluid outlet path into the lumen of the tube32, and a collection connector 48 providing a fluid outlet path from thelumen of the tube. These infusion and collection connectors arepreferably isolated from each other so that the fluid may be infusedthrough the infusion connector and simultaneously removed through thecollection connector. The distance l₁ between the infusion port 46 andaccess tube 32 is preferably minimized, usually being 1 cm or less,while the distance f₂ between the infusion port 46 and collection port48 may be from 0 mm to 2 cm, preferably being 1 cm or less. Whileillustrated on opposite sides of the hub 34, the infusion port 46 andcollection port 48 may have any relative radial orientation, with analignment of both ports on the same side of the hub being presentlypreferred.

[0082]FIG. 4A depicts a single lumen access tube 50 accessing the breastduct D and positioned with its distal end 14 distal to the ductalsphincter S of the breast duct. FIG. 4B depicts filling the breast ductD and allowing the fluid to remain in the duct for a preselected time.FIG. 4C depicts removing the infused fluid mixed with ductal fluidthrough the access tube that remains in the duct during the filling ofthe duct and collecting of the fluid. FIG. 4D depicts a catheter 52having infusion and collection arms 54 and 56 exterior to the accessedduct for separately infusing fluid into the duct and collecting fluidfrom the duct. The invention provides a device having an access tube, adistal end, a single lumen, dimensions to permit insertion of the devicedistal to the ductal sphincter. The device also has an infusionconnector, a collection connector, and that the infusion and collectionconnectors are isolated.

[0083]FIG. 6 depicts an alternative ductal access device 72 with stopcocks 74 and 76 to control the fluid flow into and out from an accessedduct. A syringe 78 for infusing fluid into the duct is connected to onearm 80 of an access tube 82. A collection tube 86 is connected toanother arm 84 connected to the access tube 82. The access tube may havesingle, dual, or multiple lumens as described elsewhere herein. FIG. 7depicts the device of FIG. 6 accessing a breast duct BD. Fluid may beinfused from syringe 78 with stopcock 76 open and stopcock 74 closed.After infusing a desired volume as set forth above, and optionallymassaging the breast, stopcock 74 may be opened and fluid collected inpassive receptacle 86 (FIG. 6) or actively withdrawn using a secondsyringe 88 to apply a vacuum through the collection arm 84.

[0084]FIGS. 8 and 8A-8C illustrate a dual lumen catheter 100 havinglumens 102 and 104 that access the breast duct. A reduced diameterregion 106 accesses the breast duct and the catheter resides in the ductat a depth of about 3.5 cm. The reduced diameter portion 106 of thecatheter has three lumens 103, 105, and a third central lumen whichreceives a fixed stiffening wire 108 (FIG. 8B). The proximal part of thecatheter 100 that does not access the breast duct is depicted in crosssection in FIG. 8A having interior lumen 104 and an annular lumen 102both which provide fluid flow (either collection or infusion) during useof the catheter to retrieve cellular material from the breast duct.Proximal connector 110 is near a proximal end of the proximal portionand branches into an infusion arm 112 and aspiration arm 114, eachconnected to one of the lumens 102 and 109. The distal portion 106 andproximal portion meet at shoulder 116 where the lumens 102 and 104 makea transition to annular lumens 103 and 105 (FIG. 8B). Distal tip 120 maybe atraumatic for entry into a ductal orifice and ductal lumen. Usually,side ports 122 will be formed on the distal section 106 to permit fluidinflow and outflow from the lumens 103 and 105, respectively.

[0085]FIGS. 9A and 9B depict two formats of transition between a distalend of an access tube 130 which accesses the breast duct and theproximal end which resides outside the breast duct. Shoulder 132 in FIG.9A has a graduated transition, and shoulder 134 in FIG. 9B has a steppedtransition.

[0086] The invention also provides systems and kits 60 for collectingcellular material from a breast duct. FIG. 5 depicts a system comprisingan access device 62, such as a single lumen catheter having infusion andcollection arms 64 and 66 outside the ductal access portion of thecatheter, optionally a premeasured solution to infuse into the duct andinstructions for use of the catheter and wash fluid to access a breastduct and retrieve cellular material, e.g., contained in syringe 70. Thesystem 60 includes instructions setting forth any of the methodsdescribed herein, such as the method for obtaining cellular materialfrom a human breast milk duct comprising introducing a ductal accessdevice having at least one lumen therethrough into a duct, introducing awash fluid through the access device lumen into the milk duct, wherein avolume of at least 2 ml is present within the duct for a preselectedtime; and collecting at least a portion of the wash fluid from the ductthrough the lumen of the access device. Wash fluid can be included inthe kit and can comprise for example, saline, phosphate buffered saline,a nonabsorbable fluid, an isotonic solution, an osmotic solution, ahypotonic solution, a hypertonic solution, a protein, a colloid, asugar, a polymer, mannitol, sorbitol, glucose, glycerol, sucrose,raffinose, fructose, lactulose, sodium chloride, polyethyleneglycol(PEG), maltodextrin, dextran (e.g. dextran 70), hydroxyethyl starch,fluid gelatin, a synthetic colloid, an antibody, a binding protein, oralbumin.

[0087] Other ductal access systems available comprise a ductal accessdevice as a container holding a premeasured volume of ductal wash fluid.The ductal access device comprises an access tube having a distal end,at least one lumen therethrough, and dimensions which permitintroduction of the distal end through a ductal orifice and positioninga distal end thereof distal to the ductal sphincter of a human breast.The device may also comprise a means on the access tube for positioningthe distal end distal to the ductal sphincter. The container cancomprise a syringe for connection to the first side port. Thepre-measured volume is in the range from 2 ml to 100 ml. The wash fluidcan comprise for example, saline, phosphate buffered saline, anonabsorbable fluid, an isotonic solution, an osmotic solution, ahypotonic solution, a hypertonic solution.a protein, a colloid, a sugar,a polymer, mannitol, sorbitol, glucose, glycerol, sucrose, raffinose,fructose, lactulose, sodium chloride, polyethyleneglycol (PEG),maltodextrin, dextran (e.g. dextran 70), hydroxyethyl starch, fluidgelatin, a synthetic colloid, an antibody, a binding protein, oralbumin.

[0088] Another ductal access system comprises a ductal access devicecomprising an access tube having a distal end, a single lumentherethrough, and dimensions which permit introduction of the distal endthrough a ductal orifice and positioning a distal end thereof distal tothe ductal sphincter, an infusion connector providing a fluid flow pathinto the lumen of the access tube; and a collection connector providinga fluid outlet path from the lumen of the access tube, said infusion andcollection connectors being isolated from each other so that fluid maybe infused through the infusion connector and simultaneously removedthrough the collection connector, the system also including a containerholding a premeasured volume of ductal wash fluid. The container cancomprise a syringe for connection to the first side port, and thepremeasured volume can be in the range from 2 ml to 100 ml. The fluidcan comprise saline, phosphate buffered saline, a nonabsorbable fluid,an isotonic solution, an osmotic solution, a hypotonic solution, ahypertonic solution, a protein, a colloid, a sugar, a polymer, mannitol,sorbitol, glucose, glycerol, sucrose, raffinose, fructose, lactulose,sodium chloride, polyethyleneglycol (PEG), maltodextrin, dextran (e.g.dextran 70), hydroxyethyl starch, fluid gelatin, a synthetic colloid, anantibody, a binding protein, or albumin.

[0089] Another ductal access system can comprise a ductal access devicecomprising a hub having an internal elongate manifold, a lower port at abottom of the manifold, and first and second side ports spaced above thelower port; and an access tube having a distal end, a proximal end, alumen therethrough, and dimensions which permit introduction of thedistal end through a ductal orifice and a positioning a distal endthereof distal to the ductal sphincter of the human breast, wherein theproximal end of the tube is attached to the lower port of the hub, theductal access system comprising also a container holding a premeasuredvolume of ductal wash fluid. The container can comprise a syringe forconnection to the first side port. The pre-measured volume is in therange from 2 ml to 100 ml. The ductal access fluid can comprise, e.g.,saline, phosphate buffered saline, a nonabsorbable fluid, an isotonicsolution, an osmotic solution, a hypotonic solution, a hypertonicsolution, a protein, a colloid, a sugar, a polymer, mannitol, sorbitol,glucose, glycerol, sucrose, raffinose, fructose, lactulose, sodiumchloride, polyethyleneglycol (PEG), maltodextrin, dextran (e.g. dextran70), hydroxyethyl starch, fluid gelatin, a synthetic colloid, anantibody, a binding protein, or albumin.

[0090] Additionally, a ductal access system is provided comprising aductal access catheter comprising a catheter body having a distal endand a proximal end and including at least a distal portion and aproximal portion, wherein the distal portion has a cross-sectionalgeometry which can be inserted through a ductal orifice into a ductallumen of a human breast, wherein the proximal portion has across-sectional geometry which inhibits insertion through the ductalorifice and into the ductal lumen; and wherein the catheter body has atleast an infusion lumen and an collection lumen each of which has adistal port near a distal end of the distal portion and a proximalconnector near a proximal end of the proximal portion, the ductal accesssystem comprising also instructions for use setting forth a method forlavage of a ductal network in a human breast including introducing awash fluid through the infusion lumen into the ductal network andwithdrawing the wash fluid and substances borne by the wash fluid fromthe ductal network through the collection lumen.

[0091] At least one of the lumens of the breast duct access device canhave a means to control the fluid flow through that lumen. The inflowlumen can be connected to a syringe or other infusion mechanism forinfusing lavage fluid into the breast duct. The outflow lumen can beconnected to a collection tube, a collection syringe, or othercollection means for collecting the lavage fluid after it has mixed withthe ductal fluid in the breast duct. The means to control the fluid flowin a lumen can be, e.g. a stopcock, valve or other control unit that iscapable of closing or opening a port of the lumen. The lumens themselvesmay be compressible or pinchable with fingers or clamps or otherpinching or compressing mechanism. A stopcock may be attached at a lumenof a dual lumen catheter to control the fluid flow through that lumen.An inflow lumen may have an inflow stop cock to control fluid flowthrough an inflow port. An outflow lumen may have an outflow stop cockto control fluid flow through an outflow port. The device can havestopcocks (or other means to control fluid flow) on both an inflow andan outflow lumen. These control units, valves or stopcocks are capableof operating separately, e.g. so that when an inflow port is opened, anoutflow port can be closed, etc. Thus, patterns of control of the fluidflow in a lavage procedure of a breast duct can include, e.g. an openinflow when an outflow is closed, an open inflow when an outflow isopened, a closed inflow when an outflow is opened, and a closed inflowwhen an outflow is closed. The catheter may have the graduated ductprobe attached to it at the distal end for accessing the duct. Where theprobe is unattached to the catheter, and is used for dilating theorifice, the catheter can have a tip appropriate for accessing thedilated duct upon removal of the probe.

[0092] Lavage fluid can be a saline solution, e.g. normal saline, orphosphate buffered saline (PBS), or other fluid capable and suitable forwashing a body duct. The lavage fluid will generally be biocompatibleand nontoxic to the patient. The lavage fluid can further compriseadditives, e.g. gas, particles or other fluids. These additives to thelavage fluid may have various purposes, however, during a lavageprocedure, the preeminent purpose will generally be to increase arecovery of fluid and/or cellular material, and/or molecular speciesfrom the ducts. Thus, such gas may provide a cleansing action on theductal walls for example, encouraging ductal epithelial cells locatede.g. in a lesion in the duct to shed and be retrievable during thelavage procedure. Similarly, particle additives may serve to encouragefluids, cellular material and/or molecular species to follow theparticles in the flow of lavage fluid through the ducts and be retrievedin the lavage procedure. Such additives as detergents, e.g. agentstending to form micelles for collecting ductal contents including cellsand molecular species may provide additional yields of cells, molecularspecies and fluids in a lavage procedure. The gas can be ambient air ora related product, and the lavage fluid can comprise the air mixed inwith the fluid for delivery into the duct. The presence of air or othergas may serve to increase the retrieval of cells and fluid as comparedto a procedure conducted using lavage fluid alone. The air can bebubbled into the fluid, or introduced into the fluid mixture by otherstandard means. The air may also be mixed into the lavage fluid as thelavage fluid is delivered into the duct, e.g. where the infusion portallows for delivery of both air and lavage fluid into the inflow lumenswhere the two mix and both are delivered to the accessed ducts.

[0093] The lavage fluid can further contain other agents that may aid inthe retrieval of fluid or cells or both from the duct or may serve someother useful purpose in the procedure. For example, the lavage fluid mayinclude or be preceded by or followed by such other agents that may aidin the retrieval of fluid or cells or both from the duct, or may servesome other useful purpose in the procedure. Such other agents can be,for example, an oncotic and/or osmotic agent capable of increasing theamount of collectable fluid in the ductal lumen, or a detergent that canhelp wash out more cells, or an agent that may help detach more cellsfrom the duct wall into the ductal lumen (e.g. trypsin, collagenase, orEDTA). The agent can be an oncotic agent and/or an osmotic agent orboth. Oncotic and osmotic agents are agents that retain fluid aroundthem or draw fluid to them. The agent can be soluble, e.g. soluble in asuitable solvent, including e.g. water, buffered water, or a salinesolution. Preferably the solvent is biologically compatible withmammals. Suitable solvents will be those that both effectively dissolvethe agent and are not toxic to a mammal. The agent can be a molecularspecies including e.g. a protein, colloid, sugar, or polymer. The agentcan be mannitol, sorbitol, glucose, glycerol, sucrose, raffinose,fructose, lactulose, sodium chloride, albumin, polyethyleneglycol (PEG),maltodextrin, dextran (e.g. dextran 70), hydroxyethyl starch, fluidgelatin, or a synthetic colloid. Agents including e.g. mannitol,sorbitol, PEG, glycerol are described in THE MERCK INDEX, 12^(th) ed.1996, Whitehouse Station, NJ. Others, including maltodextrin, dextranand others are available from Aldrich Chemical Co. in Milwaukee, WI orSigma Chemical Co. in St. Louis, Mo. The molecular weight of a suitableoncotic agent can be determined as optimally within the range of themolecular weights of suitable oncotic agents available.

[0094] Where the agent in the lavage fluid is a protein, the protein canbe a binding protein or an antibody. The binding protein can be albumin.The antibody can be capable of binding an epitope found in a breastduct, e.g. an epithelial cell surface marker or cancer cell marker, etc.Where the agent is a protein, the protein is of a molecular weight inthe neighborhood of albumin or higher, so that it is capable of actingas an oncotic agent in the lumen of the milk duct. Suitable antibodiesare commercially available. Also the agent can be a mixture of osmoticand/or an oncotic agents. The oncotic agent and/or osmotic agent cancomprise a mixture of any two or more osmotic and/or oncotic agents,e.g. mannitol, sorbitol, glucose, glycerol, sucrose, raffinose,fructose, lactulose, sodium chloride, albumin, polyethyleneglycol (PEG),maltodextrin, dextran (e.g. dextran 70), hydroxyethyl starch, fluidgelatin, an antibody or a synthetic colloid. Preferably the agent is nottoxic to a mammal, particularly not toxic to a human. The agent can bean agent not capable of freely diffusing into or beyond the cells thatline the milk ducts of the breast. The agent can also be an agent notcapable of absorption into the cells within the duct. For example, theagent can have a molecular weight large enough to make absorption ordiffusion into the breast duct lining, cells or interstitial spacebeyond the lining improbable.

[0095] The method provides that the catheter is used to access thebreast duct after being primed (i.e. filled) with lavage fluid with bothoutflow and inflow ports closed. The outflow stop cock can be opened andthe fluid allowed to infuse into the duct from the outflow to flush theoutflow port at the catheter tip and make it ready to receive the ductalfluid and wash fluid into the outflow lumen during the lavage procedure.The outflow port at the stopcock is then closed by closing the outflowstopcock. The inflow port is opened by opening the inflow stopcock. Washfluid is infused into the breast duct until resistance is met. Theamount of this first infusion bolus will vary depending on the size ofthe breast duct being infused. The inflow port is then closed by closingthe inflow stopcock. The breast is massaged by applying manual externalpressure on the breast tissue. The outflow lumen is opened and thebreast is massage and squeezed and fluid is collected in the collectionreceptacle attached to the outflow lumen. The process can be repeatedseveral times. Subsequent to the first larger bolus of wash fluid,lesser amounts of wash fluid can be infused into the duct and collectedin the outflow collection receptacle as just described.

[0096] A practitioner desirous of increasing a yield of fluid and cellsfrom a lavage of a patient's breast ducts, and/or desirous of retrievingfluid and cells from distal regions of the ductal architecture, canmassage the breast of the patient once the fluid has been infused intothe duct. The fluid is infused into the duct (with the outflow portclosed) to a point of resistance and then the inflow port is closed. Thebreast can be massaged at this point to effect a mixing of the ductalfluid with the lavage fluid, and to generally provide some gentledisruption of ductal cells in the duct and allow them to enter the fluidmix. The outflow port can be opened at this point, and allow themassaging can continue, it can be supplemented with a squeezing orcompressing of the breast, i.e. from the base of the breast upwardstowards the nipple in order to encourage as much fluid to escape via theoutflow lumen and into the collection receptacle.

[0097] Modifications to the method of lavage can include that thepatient is seated during the lavage procedure, rather than the standardor classic supine (face up) position. In addition, the patient may belavaged in a prone position, face down, with nipples and breast down.The prone face down position takes advantage of gravity and allows thebreast ducts to drain into the collection receptacle during theprocedure when the outflow port is open. Thus, the lavaging procedurecan include infusing the breast duct with a wash fluid through an openinflow lumen while an outflow lumen is closed; closing the inflow lumenwhen the duct is filled; squeezing or massaging the breast or both; andopening the outflow lumen to collect the wash fluid.

[0098] The cells collected can comprise ductal epithelial cells; theductal fluid collected can comprise molecular and cellular material.Analysis of the ductal epithelial cells and/or the molecular andcellular material in the ductal fluid can proceed as described belowdiscussing the diagnostic methods possible of these collected materials.The collected cells and fluid and fluid components can be analyzed, e.g.as described or suggested herein. The lavage fluid including the ductalcells can be analyzed for diagnostic purposes. Conditions in a breastmilk duct that are desirable to diagnose include a cancer or precancercondition. The precancer condition can include atypical ductalhyperplasia (ADH) or low grade ductal carcinoma in situ (LG-DCIS). Thediagnostic agent may also have the ability to diagnose other breastrelated conditions, including, e.g. fibrotic, cystic or conditionsrelating to lactation. Diagnostic agents can be mixed with the ductalfluid (either in the lavage procedure, or after the fluid is collected).

[0099] The diagnostic agents can include tags for detecting lesions orother abnormalities or characteristic anatomical or molecular identitiesin the breast ducts, including e.g. chemical tags or antibodies. Thetags may provide the capacity for visualizing the location of a lesion,including, e.g. fluorescent tags, or biotinylated tags. Antibodies canalso be tagged so that the binding antibody is identifiable. Antibodiescan be whole antibodies, or parts of antibodies including, e.g. Fabfragments, heavy and/or light chain fragments, single chain antibodiesand other modified antibodies commonly known about and used in the fieldof antibody-assisted diagnosis. Diagnostic antibodies or other tags canbe to a number of markers, including e.g. the following cancer markersthat are exemplary and may be used to analyze the breast duct condition.Standard assay procedures for identifying the markers can be used.analyzed for the presence of soluble factors or other components thatmight indicate the presence of cancerous or precancerous ductalepithelial cells in the duct. The epithelial cells retrieved from thebreast duct can be analyzed for protein markers, nucleic acid markers,chromosomal abnormalities, or other characteristic changes that wouldsignal the presence of cancerous or precancerous cells. In addition,other cells found in the duct can also be analyzed, e.g. for an increaseor decrease in these cells as compared to normal ductal fluid, or forqualities of these cells themselves. Thus, the condition of the breastduct can be analyzed e.g. for soluble protein content or presence ofother ductal fluid components, including also secreted products ofductal epithelial cells) or the ductal epithelial cells themselves canbe analyzed, for example, for cell morphology, for protein markers, fornucleic acid markers, and for biochemical markers.

[0100] In addition, any of the cells of the duct can be analyzed formorphological abnormalities in cell components, including, e.g.morphological abnormalities of the nucleus, cytoplasm, Golgi apparatusor other parts of a cell. The cells can be analyzed for whether they door don't aggregate (e.g. in clumps) or by making comparisons of theductal epithelial cells with other cell types retrieved in the ductalfluid (e.g. macrophages, lymphocytes, foam cells and other possiblecomponents of ductal fluid). The ductal epithelial cells can be analyzedfor their molecular contents or the morphology of the ductal epithelialcells, including, e.g. protein markers, nucleic acid markers,biochemical markers in the cells or on the cell surfaces or for anyevidence of neoplasia.

[0101] In addition to some markers discussed and/or articles or bookscited on breast cancer and breast precancer markers, including markerslisted in Porter-Jordan and Lippman, “Overview of the biological markersof breast cancer”, Hematology/Oncology Clinics of North America vol. 8(1):73-100, 1994), the following cancer markers are listed here asexemplary and may be used as well as other markers to analyze thecondition of a breast duct, including analysis of the ductal contents(including fluid and cells). Standard assay procedures for identifyingthe markers can be used, including antibodies or other binding partners,labels, stains, pattern analysis (for cells and cell components), and ingeneral any other chemical or visual identification techniques.

[0102] Markers that are presently being studied by researchers presentlyinclude, carcinoma embryonic antigen (CEA), prostate specific antigen(PSA) Erb B2 antigen, gross cystic disease fluid protein-T5 (GCDFP-15),and lactose dehydrogenase (LDH). For CEA see Imayama et al, Cancer 1996,78(6):1229-34; Inaji et al, Cancer 1987,60(12):3008-13; Mori Int CongerSeer 1989, 807:211-8; Inaji, et al, An To Kagaku Ryoho 1991,18(2):313-7; Yayoi, et al Gan To Kagaku Ryoho 1994, 21 Suppl 2:133-9;Mori, et al Jpn J Clin Oncol 1989,19(4):373-9; Foretova, et al Proc AnnuMeet Am Soc Clin Oncol 1995,14:A101; and Nishiguchi, et al Rinsho Byori1992,40(1):67-72. For PSA see Foretova, Garber Lancet1996,347(9015):1631; Sauter et al, Cancer Epidemiology, Biomarkers &Prevention. 5(12):967-70, 1996; Sauter and Daly (1996) Proc Annu Meet AmAssoc Cancer Res 37:A1458; and Foretova and Garber (1996) Proc Annu MeetAm Assoc Cancer Res 37:A1446. For Erb B2 see Motomura (1995) BreastCancer Res and Treat 33:89-92; and Inaji et al (1993) Tumour Biol 14:271-8. For GCDFP-15 see Petrakis et al (1994) Proc Annu Meet Am AssocCancer Res 35:A1698. For LDH see Mannello et al (1995) Cancer 76:152-4;and Kawamoto (1994) Cancer 73:1836-41.

[0103] Chromosomal abnormalities in ductal epithelial cells can alsoprovide information and act as a marker to identify cancer or precanceras described in Mark et al (1999) Cancer Genet Cytogenet 108:26-31;Lundlin and Mertens (1998) Breast Cancer Res Treat 51:1-15; Newsham(1998) Am J Pathol 153:5-9; Larson et al (1998) Am J Pathol 152:1591-8;Adelaide et al (1998) Genes Chromosomes Cancer 22:186-99; Fejzo et al(1998) Gene Chromosome Cancer 22:105-113; Dietrich et al (1998) HumPathol 12: 1379-82; Cavalli et al (1997) Hereditas 126:261-8; Adeyinkaet al (1997) Cancer Genet Cytogenet 97:119-21; Afify and Mark (1997)Cancer Genet Cytogenet 97:101-5; Brenner and Aldaz (1997) Prog Clin BiolRes 396: 63-82; Mark et al (1997) Ann Clin Lab Sci 27:47-56; and Fabianet al 1993 J Cellular Biochemistry 17G:153-16.

[0104] In addition, exemplary markers are described in Masood,(Prediction of recurrence for advanced breast cancer. Traditional andcontemporary pathologic and molecular markers) Surgical Oncology Clinicsof North America. 4(4):601-32, 1995; Lopez-Guerrero et al (1999) JHematother 8(1):53-61; Marjumdar and Diamandis (1999) Br J Cancer79(9-10):1594-602; Balleine et al (1999) Br J Cancer 79 (9-10):1564-71;Houston et al (1999) Br J Cancer 79(7-8):1220-6; Nikolic-Vukosavljevicet al (1998) Tumori 84(6):691-4; Maguire et al (1998) Int J Biol Markers13(3):139-44; Steams et al (1998) Breast Cancer Res Treat52(1-3):239-59; Eiriksdottir et al (1998) Eur J Cancer 34(13):2076-81,and U.S. Pat. No. 5,169,774. Many known breast cancer markers arediscussed and described in readily available medical textbooks on breastcancer. Other markers are also listed herein.

[0105] The morphology of the cells or cellular contents retrieved in theductal fluid and wash fluid may also be examined. The cellular contentscan include, e.g. protein, nucleic acid, or other molecular markers inthe cells. Cell morphology can serve to establish whether the ductalepithelial cells are normal (i.e. not precancerous or cancerous orhaving another noncancerous abnormality), precancerous (i.e. comprisinghyperplasia, atypical ductal hyperplasia (ADH) or low grade ductalcarcinoma in situ (LG-DCIS)) or cancerous (i.e. comprising high gradeductal carcinoma in situ (HG-DCIS), or invasive carcinoma). Analysis ofcell contents may serve to establish similar staging as established bymorphology, capturing generally a progression of a precancerous orcancerous condition in the cells.

[0106] Administering fluid to the ductal lumen for the purpose ofcollecting that fluid mixed with the fluid from the duct is complicatedby the fact that absorbable wash fluids are partly absorbed into thebreast from the duct. Thus, the fluid retrieved is less than thatinfused, even considering that it includes the ductal fluid that wasresiding in the duct. Administering an agent in the wash fluid that iscapable of increasing or maintaining the fluid volume in the duct is agreat advantage to the process. Thus, the invention providesadministering a nonabsorbable fluid or a fluid that actually draws fluidto it, e.g. an oncotic or osmotic fluid in the process of collectingfluid from the duct. Administering the nonabsorbable fluid has theadvantage also of providing the practitioner with a way to monitor orstandardize the ductal fluid and cellular return in any given volume offluid infused and retrieved. For example 10 ml of the nonabsorbablefluid is administered to the duct, and 9.5 ml of that fluid iscollected. Maybe 100 epithelial clusters are contained in the fluidcollected. This information can be noted, and during future procedureson that same duct can be compared. The advantage of using anonabsorbable is that the ductal fluid yield may be increased with theretrieval of most or all of the infused fluid, and the practioner willbe able to keep track of the amount infused versus the amount collected.

[0107] A nonabsorbable fluid can be used in order to provide astandardization to the process so that the amount infused can becorrelated with the amount collected, knowing that since the fluidcannot be absorbed in the duct, and collecting of all or most of thefluid that is infused is possible.

[0108] Identification of the location of the ducts prior to accessingthem can be made as described in PCT application to the Regents of theUniversity of California at Los Angeles filed Sep. 15, 1998 to Barsky etal entitled “Methods and Kits for Identifying Ductal Orifices in aNipple”, or U.S. Ser. No. 09/153,564 filed Sep. 15, 1998 to Barsky etal.

[0109] The agent is an agent capable of in effect increasing the amountof collectable fluid in the ductal lumen. Thus the agent can be anonabsorbable agent or fluid or an oncotic agent and/or an osmotic agentor a combination of two or all three. Oncotic and osmotic agents areagents that retain fluid around them or draw fluid to them. The agentcan be soluble, e.g. soluble in a suitable solvent, including e.g.water, buffered water, or a saline solution. Preferably the solvent isbiologically compatible with mammals. Suitable solvents will be thosethat both effectively dissolve the agent and are not toxic to a mammal.

[0110] The agent can be a molecule including e.g. a protein, colloid,sugar, or polymer. The agent can be mannitol, sorbitol, glucose,glycerol, sucrose, raffinose, fructose, lactulose, sodium chloride,albumin, polyethyleneglycol (PEG), maltodextrin, dextran (e.g. dextran70), hydroxyethyl starch, fluid gelatin, or a synthetic colloid. Agentsincluding e.g. mannitol, sorbitol, PEG, glycerol are described in THEMERCK INDEX, 12^(th ed.) 1996, Whitehouse Station, N.J. Others,including maltodextrin, dextran and others are available from AldrichChemical Co. in Milwaukee, Wis. or Sigma Chemical Co. in St. Louis, Mo.The molecular weight of a suitable oncotic agent can be determined asoptimally within the range of the molecular weights of suitable oncoticagents available.

[0111] Where the agent is a protein, the protein can be a bindingprotein or an antibody. The binding protein can be albumin. The antibodycan be capable of binding an epitope found in a breast duct, e.g. anepithelial cell surface marker or cancer cell marker, etc. Where theagent is a protein, the protein is of a molecular weight in theneighborhood of albumin or higher, so that it is capable of acting as anoncotic agent in the lumen of the milk duct. Suitable antibodies arecommercially available.

[0112] Also the agent can be a mixture of osmotic and/or an oncoticagents. The oncotic agent and/or osmotic agent can comprise a mixture ofany two or more osmotic and/or oncotic agents, e.g. mannitol, sorbitol,glucose, glycerol, sucrose, raffinose, fructose, lactulose, sodiumchloride, albumin, polyethyleneglycol (PEG), maltodextrin, dextran (e.g.dextran 70), hydroxyethyl starch, fluid gelatin, an antibody or asynthetic colloid.

[0113] The agent can be an agent not capable of freely diffusing into orbeyond the cells that line the milk ducts of the breast. The agent canalso be an agent not capable of absorption into the cells within theduct. For example, the agent can have a molecular weight large enough tomake absorption or diffusion into the breast duct lining, cells orinterstitial space beyond the lining improbable.

[0114] Whether an agent is capable capable of increasing or at leastmaintaining the amount of collectable fluid (with relation to the amountof fluid infused) in the ductal lumen can be determined byexperimentation to identify whether collectable fluid in the duct isincreased upon administration of an agent as compared to administrationof a control isotonic solution to a neighboring control duct. Likewisethe best volume and concentration of the agent can be determined by acomparison of the amount of collectable fluid yielded with a change in avariable such as a volume or concentration of agent administered. Theagents including nonabsorbable fluid and/or oncotic and/or osmoticagents to be tested can be delivered to the duct of a human, rat,rabbit, pig or other appropriate mammal, and the ductal fluid can becollected. Where the fluid yield is greater than control fluid collectedfrom a neighboring duct (after injection of a control solution,preferably of equal volume as the tested solution), that agent issuitable for use in the method. The increased fluid amount should be atleast 50% and more preferably close to 100% of an increase of fluidcollectable from the ducts that are compared. In the case where thepractitioner seeks to increase the amount of fluid collected from theamount infused, the fluid yield from the duct administered with theagent being tested can be several fold that of the control fluid yield.Where the goal is merely to provide for a collection fluid amount thatis close to the amount infused, the parameters for success are that theamount of fluid collected from the duct after infusion of a set aliquotof fluid is closer to the amount infused that would have been possibleif the infusion fluid had been an absorbable fluid such as saline. Sucha comparison can be tested by doing a control infusion and collection ina duct using e.g. saline and then repeating the procedure in the sameduct using a nonabsorbable fluid, e.g. a PEG containing fluid or thelike.

[0115] The appropriate concentration and volume of oncotic agent and/orosmotic agent in solution injected into a duct can be determined byroutine experimentation including cannulation or catheterization ofmammalian nipples (e.g. rat, rabbit, pig or human nipples) to determineat which concentration and volume the agent in solution yields the mostvolume of fluid collectable from the duct as compared to the fluidcollectable from a control duct. Experiments can be designed for testinga variety of oncotic and/or osmotic agents, concentrations, volumes, andmixtures of agents in all varieties of mammals having breast ducts.

[0116] Fluid collected from the milk ducts, can include constituents ofbiological fluids, e.g. those typically found in breast duct fluid, e.g.water, cells, cellular markers, molecular markers, nucleic acids,proteins, cellular debris, salts, or organic molecules. Theseconstituents can be analyzed by any appropriate method depending on thepractitioner's purposes in obtaining the fluid.

[0117] The fluid can comprise cells including e.g. epithelial cells andabnormal cells. The cells can be analyzed for cellular, protein, nucleicacid, or other molecular markers or for shape or other abnormalities.Analysis of the cells can provide diagnostic or prognostic informationfor an evaluation of the condition of the breast or breast ducts.Removal of cells can be conducted in the presence of the agent, andpreferably the action of the osmotic and/or oncotic agent provides forremoving cells that can be analyzed.

[0118] The invention includes a kit for increasing the amount of fluidcollectable from a milk duct of a breast comprising an nonabsorbableagent and/or an osmotic agent and/or an oncotic agent, a medical toolfor delivering the agent to the ductal lumen, and instructions for use.The nonabsorbable agent and/or oncotic and/or osmotic agent can be thosedescribed herein or other comprising like properties and/or functions ina breast duct. The medical tool can be any tool that enables delivery ofsuch agent. The instructions can direct a protocol for administrationincluding how to administer the agent, how much time to wait beforecollecting the fluid, how to collect the fluid, and how to analyze thefluid collected.

[0119] The retrieved fluid can comprise constituents of the breast milkduct fluid, e.g. including water, cells, cellular markers, molecularmarkers, nucleic acids, proteins, cellular debris, salts, or organicmolecules. Analyses can be made that identify molecular or cellularmarkers, cellular characteristics, e.g. by cytology, and for making anyother assessment of any of the constituents of the fluid. Cells that areretrieved and analyzed can be epithelial cells or abnormal cells.

[0120] Multiple lumen ductal access catheters, having more than onelumen in the access portion of the catheter, according to the presentinvention will comprise a catheter body having a distal end and aproximal end and including at least a distal portion and a proximalportion. The catheter will have at least two continuous lumens extendingthrough both the proximal and distal portions. The lumens can be fluidcarrying, and fluid can pass from the proximal portion to the distalportion of one lumen and from the distal portion to the proximal portionof a second lumen. The distal portion has a cross-sectional geometrywhich can be inserted through a ductal orifice into a ductal lumen of ahuman breast for the purpose of lavaging the breast duct. The proximalportion has a cross-sectional geometry which inhibits insertion throughthe ductal orifice and into the ductal lumen thereby placing limits onthe extent that the catheter penetrates the breast duct during thelavage procedure. The lumens of the catheter are an infusion lumen andan aspiration or collection lumen. Each lumen has a distal port near thedistal end of the distal portion of the catheter. One distal port is forinfusing liquid into the duct (a port on the infusion lumen). The otherdistal port is for aspirating or collecting fluid from the duct (a porton the aspiration lumen). The catheters also have a proximal connectornear a proximal end of the proximal portion for connecting e.g. to afluid receptacle that holds fluid for infusion into the duct (e.g. awash or lavage fluid) and for connecting to a collection receptacle forcollecting the contents of the duct that are aspirated in the aspirationlumen (e.g. a syringe that can both aspirate and collect the ductalfluid and/or ductal contents).

[0121] The ductal access catheter will have a total length in the rangeof from about 2-cm to about 60-cm, usually about 30 cm to about 45-cm.The length of the proximal portion will typically be in the range ofabout 15-cm to about 50 cm, more typically in the range from about 30 cmto about 40 cm. The distal portion will typically be in the range fromabout 2.5-cm to about 8 cm, more typically in the range from about 3.0cm to about 5.5 cm.

[0122] The proximal and distal portions will preferably be joined toeach other with an intermediate zone between them to accommodate thedifference in cross-sectional geometry between the proximal and distalportions. The intermediate zone can be a stepped decrease incross-sectional geometry from proximal to distal portions, or may be agradual decrease in cross-sectional geometry from proximal to distalportions. The body segments can be joined in any conventional manner toeach other (and/or to the either end of the element creating theintermediate zone) including methods such as heat fusion, adhesivebonding, coextrusion, or the like. In the exemplary embodiment, thedistal and proximal portions will be coextruded and the coextrusionprocess will generate the intermediate zone in accommodating thedifferential cross-sectional geometry of the proximal to the distalportions.

[0123] The catheter can have the distal portion of the catheter bodystiffened over at least a part of its length to facilitate insertionthrough the ductal orifice and into the ductal lumen. The stiffeningeffect can be created by insertion of a third lumen in the distalportion, the third lumen comprising a wire. The wire can be made of somerelatively stiff metal, e.g. tungsten or steel. The stiffened distalportion of the catheter body can have an average bending stiffness inthe range from about 0.010 inch-lbs to about 0.5 inch-lbs. Typically thebending stiffness of the distal portion will be about 0.105 inch-lbs.

[0124] The catheter may be composed of any biologically compatiblepolymeric resins or metal having suitable characteristics when formedinto the tubular catheter portions. Exemplary materials includepolyvinyl chloride, polyethers, polyamides, polyethylenes,polycarbonate, polyurethanes, copolymers thereof and the like. Thedistal portion may be formed of the same or different material as theproximal portion. Although a stiffening wire may be placed in the distalportion, if the stiffening wire is not present, the distal portion maybe composed of materials that are slightly more stiff than the materialsthat compose the proximal portion. Optionally, the distal body portionmay be reinforced with a metal or polymeric braid or other conventionalreinforcing layering.

[0125] The distal portion will be sufficiently rigid to permit axialpositioning of the distal tip in a ductal orifice with the distalportion extending either partly or wholly into the breast ductal lumen.The distal portion will typically have a hardness in a durometer rangeat least greater than that of the proximal portion, and thus generallygreater than 75 D. The hardness of the distal portion thus may be arange from about 70 D to about 90 D. The proximal portion will be moreflexible and less stiff and also less hard than the distal portion. Thedurometer of the proximal portion outer tubing can be in a range fromabout 45 A to about 100 A, and typically about 80 A. The inner tubing ofthe proximal portion can have a durometer in the range from about 50 Dto about 75 D, and typically about 63 D. The flexibility of the proximalportion provides the catheter with the advantages that the distalportion (which is stiffer) can be inserted into the breast duct,meanwhile the proximal portion can connect at its hubs with infusion orcollection apparatus and not kink during the placement of the distalportion in the breast duct. Additionally, the flexibility of theproximal portion provides the advantage that once the distal portion isplaced in the breast duct the catheter will have less tendency to pullout of the duct. The stiffness of the distal portion benefits theprocedure by allowing access into the orifice of the duct and the ductitself, an action that requires a probe-like quality of the distalportion and distal tip in order the duct to be accessed successfully.

[0126] The catheter body may further comprise other components, such asradiopaque fillers; colorants; reinforcing materials; reinforcementlayers, such as braids and helical reinforcement elements; or the like.In particular it would be possible to reinforce the distal portion inorder to enhance its duct penetration or probe-like capabilities whileoptionally limiting its wall thickness and outside diameter so that thecatheter can easily access even ducts with small ductal orifices.

[0127] The cross-sectional geometry of the distal portion of thecatheter body will be smaller than the cross-sectional geometry of theproximal portion. The cross-sectional geometry of the distal portionprovides that the distal portion can be inserted into a breast ductorifice and through the orifice into the breast duct lumen. The distalportion of the catheter body has a maximum width in the range from 0.008inches to 0.050 inches. The distal portion of the catheter body has agenerally tubular structure with a diameter in the range from about0.008 inches to about 0.035 inches. The proximal portion has across-sectional geometry which inhibits insertion of the proximalportion into the ductal orifice and the ductal lumen. Thus, the proximalportion of the catheter body has a minimum width in the range from about0.023 inches to about 0.028 inches. The proximal portion of the catheterbody has a generally tubular structure with a diameter in the range fromabout 0.030 inches to about 0.10 inches. The proximal diameter isgreater than the distal diameter by at least about 0.010 inches.

[0128] The region between the proximal and distal portions of thecatheter body provides for the reduced diameter moving from the proximalto the distal portions. The transition preserves the fluid flowcapability and communication in the lumens between the proximal anddistal portions and can provide a place to anchor or lodge a wire orstiffening lumen that extends longitudinally in the distal portion. Thetransition may be stepped, abrupt, or somewhat gradual, provided itallows the proximal portion to retain its function of inhibitinginsertion of the catheter into the duct beyond the length of the distalportion.

[0129] The ductal access catheter body can comprise at least an infusionlumen and an aspiration lumen each of which has a distal port near adistal end of the distal portion. At least one of the distal aspirationport and the distal infusion portion can be disposed on a side of thedistal portion of the catheter body. Thus one port can be a side portand one port can be and end port. The distal aspiration port and thedistal infusion port can both be located on the side of the distalportion of the catheter body. Thus, both ports for both lumens can beside ports. The distal aspiration port and the distal infusion port canbe axially aligned. Thus, the side ports can be located e.g. oppositeeach other on the on the distal portion of the catheter body at thelongitudinal position. For example, both side ports can be located about2.5 cm from the distal tip. The distal aspiration port and the distalinfusion port can be axially spaced apart. Thus, the side ports can belocated at different longitudinal positions on the distal portion, forexample one port can be located about 2.0 cm from the distal tip and oneport can be located about 2.5 cm from the distal tip. The side portsthemselves may be round or oval or any other geometric shape conduciveto fluid flow either into the duct or out from the duct. The diameter ofthe ports can be that diameter which is suitable to achieve a desiredflow rate into the duct or aspiration or collection rate out from theduct. Thus, the diameters of the ports can be in a range from about0.015 inches (0.038 mm) to about 0.022 inches (0.056 mm), most typicallyin a range from about 0.016 inches (0.041 mm) to about 0.020 inches(0.051 mm). One side port can be larger or smaller than the other,especially where such differential port size provides a desired flowrate into or out from one of the lumens, or an overall lavage efficiencyof infusion and aspiration or collection of lavage and ductal fluid.

[0130] The catheter body can include an atraumatic distal tip. The tipcan be contoured and/or rounded to reduce or eliminate trauma to theduct upon entry through the ductal orifice and penetration into theductal lumen. The tip may also be fashioned to reduce or eliminatetrauma upon withdrawal of the tool from the duct after the lavageprocedure is completed. The tip can be composed of a soft polymericmaterial, e.g. including polyvinyl chloride, polyethers, polyamides,polyethylenes, polyurethanes, copolymers thereof and the like. The tipcan have a diameter in the range from about 0.012 inches (0.031 mm) toabout 0.020 inches (0.051 mm), more typically a diameter in the rangefrom about 0.014 inches (0.036 mm) to about 0.018 inches (0.046 mm). Thelength of the tip (extending from the distal end of the distal portionof the catheter) can be in a range from about 0.25 cm to about 2.5 cm,more typically in the range from about 0.50 cm to about 1.8 cm.

[0131] The invention also provides a method for lavage of a ductalnetwork in a human breast comprising providing a catheter as anydescribed above for performing the ravage procedure. The distal portionof the catheter is inserted through a ductal orifice and into a distallumen of the ductal network. A wash fluid is introduced through theinfusion lumen into the ductal network. The wash fluid can be, e.g.saline or phosphate buffered saline, or any biocompatable fluid suitablefor washing a breast duct lumen. The wash fluid and substances borne bythe wash fluid are withdrawn from the ductal network through theaspiration lumen. The various features of the catheters described abovecan serve to facilitate the practice of the lavage procedure. Forexample, the narrow distal tip provides the catheter the ability topenetrate the ductal orifice and move the catheter into the ductal lumenfor performing the lavage procedure; the larger diameter of the proximalportion inhibits the catheter from passing too deeply into the duct, andstops the penetration of the catheter at the place where the distalportion ends and the proximal portion begins; the atraumatic tipprovides the catheter the ability to penetrate the duct without traumato the tissue walls of the ductal lumen; the stiffening material placedin at least a part of the distal portion of the catheter (e.g. astiffening wire or a supporting braid or the like) provides thepractitioner with stiffness to better control the entry and furtherpenetration of the catheter into the ductal lumen; the ports on thelumens provide the catheter the ability to infuse liquid into the ductfrom the infusion lumen and the ability to aspirate or collect fluidfrom the duct into the aspiration lumen; and where the ports are sideports, the presence of side ports may better facilitate the function ofthe ports for infusing and collecting to and from the duct.

[0132] The invention further provides a ductal access system comprisingany of the catheters describe herein and instructions for use settingforth a method for lavage of a ductal network in a human breastincluding introducing a wash fluid through the infusion lumen into theductal network and withdrawing the wash fluid and substances borne bythe wash fluid from the ductal network through the aspiration lumen,e.g. as described for the method above.

EXAMPLES

[0133] 1. Collecting Cells and Cellular Material Using Single LumenDuctal Access Device

[0134] Device as depicted in FIG. 3 was used to access breast ducts ofpatients A, B, C, D, E, F, G, and H. Before ductal access patient'snipple was cleaned with alcohol, and dekeratinized with cerumetix. Anaspiration cup was placed on the nipple and areola and the patient'snipple was aspirated to identify the breast duct and to collect fluidfor a comparison with the fluid retrieved from inside the duct. A smallquantity of fluid was observed on the nipple surface after aspirationand this fluid was collected with one or more capillary tubes placed incontact with the fluid. The aspiration fluid was preserved in apreservative solution for cells for analysis later.

[0135] Ducts that yield fluid were accessed using a dilator thatextended from the device depicted in FIG. 3, and once the duct wasaccessed by the access tube, the dilator was withdrawn. The collectiontube was closed, and the system including the infusion tube and manifoldwere primed with fluid. A total of from 10 ml to about 25 ml of salineinfusion fluid was infused into the duct until resistance was felt inthe infusion syringe. The assumption made at that point was that theduct was filled with the infusion fluid. The infusion tube was closedand the collection tube opened. The breast was massaged and thensqueezed and cloudy fluid was caused to enter the hub and begin to exitthe collection tube. To encourage the fluid to exit, the infusion tubewas opened and additional infusion fluid was pushed into the hub,causing more cloudy fluid to exit the collection tube. The followingfluid amounts refer to the procedure with Patient A. When a volume ofabout 11.5 ml of fluid was collected, the collection tube was closed andmore fluid infused until a resistance was felt in the duct. More fluidwas infused to refill the duct. The collection tube was opened, andinfusion tube was closed and the breast was massaged and squeezed toencourage more fluid to enter the hub and exit the collection tube.Additionally, the fluid was encouraged to leave the hub with aninjection of fluid from the infusion lumen. About 6 ml was collectedfrom the second filling.

[0136] The results of the nipple aspiration (NAF), first filling andsecond filling are reported below for patient A in the Table I.Patient's B, C, and D also have NAF results compared to results usingthe single lumen catheter, as depicted in Table I. Patients E, F, G andH have yields solely with respect to access and retrieval using thesingle lumen catheter. Epithelial cell clusters are defined as clustersof cells having greater than 10 epithelial cells per cluster. TABLE ITotal volume Epithelial Clusters Sample Collection collected (>10cells/cluster) Patient A; NAF (nipple aspiration >0.1 ml  1 epithelialcluster duct R2 fluid) lavage with single lumen 17.5 ml  23 epithelialclusters Patient B; NAF —  0 epithelial clusters duct L6 lavage withsingle lumen —  31 epithelial clusters Patient C; NAF 0.2 ml  0epithelial clusters duct R1 lavage with single lumen 6 ml  27 epithelialclusters Patient D; NAF <0.1 ml  0 epithelial clusters duct on leftnipple lavage with single lumen 7 ml 101 epithelial clusters Patient E;lavage with single lumen 11 ml  3 epithelial clusters duct L6 Patient F;lavage with single lumen 10.5 ml  12 epithelial clusters duct L6 duct L7lavage with single lumen 7 ml  7 epithelial clusters duct R1 lavage withsingle lumen 21 ml  6 epithelial clusters duct R2 lavage with singlelumen 7 ml  5 epithelial clusters Patient G; lavage with single lumen 6ml 400 epithelial clusters duct L6 duct R1 lavage with single lumen 8.5ml 350 epithelial clusters Patient H; lavage with single lumen 11 ml 154epithelial clusters duct L6 duct R1 lavage with single lumen 7 ml 131epithelial clusters

[0137] 2. Comparative Study: Pig Pelt Lavage with StopCock Catheter vs.Catheter without StopCocks

[0138] In order to test the efficiency of the stop cock catheter, acomparison was run comparing the amount of fluid and cells retrievedfrom a catheter which did not have stop cocks (or on which both stopcocks were kept open during the entire procedure), and a catheter havinga stop cock on the inflow lumen and a stop cock on the outflow lumenthat are opened and closed alternately during the procedure (in themanner specified below). Two experiments (experiment I and experimentII) were conducted using modified procedures A and B to testmodifications to the basic principles of the comparison. The combinedresults show the increased efficiency of using the stop cock catheter(in the manner described below in the procedure A portion of experimentsI & II) to retrieve a larger volume of infused wash fluid and a largernumber of ductal cells from the lavaged breast milk duct.

[0139] A dual lumen catheter having a support wire is used for thetests. The catheter also has a stopcock on the inflow lumen and astopcock on the outflow lumen. Frozen pig pelts were purchased fromYosemite Meats, located in Menlo Park, Calif. Procedure A was conductedusing the stopcocks controlling the opening and closing of the inflowand outflow lumens at ports located in the stopcocks. Procedure B wasconducted with both the inflow and outflow lumens open during the entireprocedure. Experiments I and II were conducted as follows:

[0140] Procedure A included the following steps:

[0141] 1. Catheter was inserted into a duct. Both inflow and outflowlumens were primed with wash fluid, and the ports closed (by placing therespective stopcocks in a closed position). The catheter was placed inthe duct.

[0142] 2. The outflow port was opened, and 1 ml of phosphate bufferedsaline (PBS) was infused into the duct to flush out the outflow lumen.The outflow port was closed.

[0143] 3. The inflow port was opened and PBS was infused into the ductuntil resistance to infusion was met. The inflow port was closed.

[0144] 4. The outflow port was opened. The breast was massaged andsqueezed. The outflow fluid was collected.

[0145] 5. The outflow port remained opened, the inflow port was opened,and 0.5 ml of fluid was infused into the inflow to flush out the outflowlumen. The inflow port was closed and the fluid collected in thecollection syringe attached to the outflow lumen.

[0146] 6. The outflow port was closed and about 1 ml of PBS was infused.The inflow port was closed. The outflow port was opened. The breast wasmassaged and squeezed, and the fluid collected. Steps 5 and 6 wererepeated until about 3 ml of fluid was collected.

[0147] Procedure B included the following steps:

[0148] 1. A dual lumen catheter (with both inflow and outflow portsopen) was inserted into the duct.

[0149] 2. The duct was infused with PBS until the fluid flow into theduct met resistance.

[0150] 3. The duct was lavaged using massaging and squeezing techniqueas the fluid was collected in the collection receptacle (located at theend of the outflow lumen).

[0151] 4. More PBS was infused (each time about 1 ml) and the massaging,squeezing and collecting proceeded. The procedure was repeated untilabout 3 ml was collected.

[0152] Procedure A (one-way flow procedure) included the followingsteps:

[0153] 1. Both the inflow and outflow lumens were primed with PBS. Theinflow and outflow ports were closed and the catheter inserted into thepig duct to a depth of about 1.5 cm.

[0154] 2. The outflow port was opened and 1 ml of PBS was infused intothe duct to flush out the outflow lumen.

[0155] 3. The outflow port was closed. The inflow port was opened. Fluidwas infused in the inflow port (about 4-5 ml) until resistance was felt.The inflow port was closed.

[0156] 4. The breast was massaged with both ports closed.

[0157] 5. The outflow port was opened and the breast squeezed to collectfluid in the collection receptacle until no more fluid comes out.

[0158] 6. The inflow port was opened and about 0.5 ml of fluid wasinfused to flush out the outflow lumen.

[0159] 7. The outflow port was closed and about 1 ml of PBS was infusedinto the duct in the inflow lumen.

[0160] 8. The inflow port was closed. The outflow port was opened, andthe breast massaged and squeezed to collect the outflow fluid. Steps 6,7, and 8 were repeated until the collection volume totaled 3 ml.

[0161] Procedure B included the following steps:

[0162] 1. Both the inflow and outflow lumens of a dual lumen catheterwere primed with PBS. The catheter tip was inserted into a breast ductof a pig pelt to a depth of about 1.5 cm. About 1 ml of PBS was infusedinto the duct through the outflow lumen to flush out the outflow lumen.

[0163] 2. PBS was infused into the inflow port until resistance wasfelt.

[0164] 3. The breast was massaged and squeezed as the duct was lavagedwith PBS. Fluid flowing to the outflow lumen was collected.

[0165] 4. More PBS was infused into the duct (each time about 1 ml) andthe duct lavaged, (using massaging and squeezing) and the fluidcollected in the collection receptacle. The procedure was repeated untilabout 3 ml of fluid was collected.

[0166] The fluid was used to prepare Cytospin® slides by taking 10 ul ofcollected fluid (plus 90 ul of PBS), using a cytospin machine to placethe fluid on a slide.

[0167] The slides are air-dried and Diff Quik® stained. The results areshown below in Table II. In all cases 3 ml of fluid was collected, butthe infusion volume varied as shown in the table. TABLE II Procedure AProcedure B infusion cell infusion cell nipple vol density nipple voldensity experiment I X2 15 ml 55% Z2 13 ml 45% X3 18 ml 65% X1 10 ml 35%Z3 13 ml 40% Z1 13 ml 45% Z5 12 ml 55% experiment II X1 14 ml 60% Z1  7ml 50% X2 12 ml 65% Z2  6 ml 50% X3 13 ml 65% Z3  6 ml 40% X4 11 ml 55%Z4  6 ml 35% average 13.5 ml   58% 8.7 ml  43%

[0168] The results indicated a 35% increased cell yield using procedureA over procedure B.

[0169] 3. Optimal Stop Cock Catheter Usage for Retrieving Cells

[0170] A procedure was developed that appeared to optimize the potentialyield of cells from the ductal fluid retrieved was a catheter-basedlavage procedure of a breast duct. Using pig pelts the followingtechnique resulted in maximized cell yield from a set volume ofcollected fluid.

[0171] 1. Inflow and outflow lumens of a dual lumen catheter having stopcocks on both lumens were primed with PBS. The inflow and outflow portswere closed and the catheter inserted into the duct to a depth of about1.5 cm.

[0172] 2. The outflow port was opened and 1 ml of PBS was infused intothe duct from the outflow lumen to flush out the outflow lumen.

[0173] 3. The outflow port was closed (using the stopcock) and theinflow port was opened. PBS was infused into the duct until resistancewas felt (about 4-5 ml of PBS). The inflow port was closed.

[0174] 4. The breast was massaged while both the inflow and outflowports were closed (using the stopcock controls).

[0175] 5. The outflow port was opened and the breast was massaged andsqueezed, and the outflow fluid was collected until no more fluid cameout.

[0176] 6. The outflow port was closed and the inflow opened, and morefluid (about 1 ml) was allowed to infuse into the duct.

[0177] 7. The inflow port was closed and the outflow port was opened.The breast was massaged and squeezed to collect the fluid.

[0178] 8. Steps 6 and 7 were repeated until a total of 3 ml of fluid wascollected.

[0179] This procedure was found to generate the best cell densitycollected in the 3 ml of fluid, and also eliminates one step fromprevious procedure A.

[0180] 4. Mannitol Solution Introduced into Breast Ducts of Live RabbitResults in Increased Ductal Fluid Collection

[0181] The objective of these experiments was to test the effects of theintroduction of a solution containing mannitol on the secretion of fluidfrom the breast ducts of live rabbits. New Zealand rabbit #3242, female,from Kraelik Farm in CA weighing 4.1 kg was used. The rabbit wasanesthetized by injection of 200 mg of ketamine and 40 mg of Zylazine. Asecond injection of 100 mg of ketamine and 20 mg of xylazine was made 2hours later to maintain the rabbit in a deep plane of anesthesia. Thethorax and abdomen of the rabbit was shaved to expose the breasts andnipples.

[0182] A single lumen blue color catheter (O.D. 0.23″ ID 0.017; O.D. atthe tip 0.011″ -0.012″) was inserted into a duct in each nipple. Threenipples were tested, and 2 ducts per nipple were accessed with acatheter. The nipples were identified A, B, and C.

[0183] A duct on nipple A was injected with 0.20 ml of a 12.5% solutionof D-Mannitol in H₂O (available from Sigma Chemicals, St. Louis, Mo.cat# M-9546 lot 6710402: C₆H₁₄O₆ FW 182.2) with a single catheter. Thecontrol duct on nipple A was injected with 0.20 ml of phosphate bufferedsaline (PBS). A microfuge tube was attached to the end of each catheterto collect out flow liquid. Ten minutes later 0.2 ml of a 12.5% solutionof D-Mannitol in H₂O was injected into the first duct and the secondduct was injected with 0.20 ml of phosphate buffered saline, for a totalvolume injected in each duct of 0.40 ml.

[0184] A duct on nipple B was injected with 0.5 ml of a 12.5% solutionof D-Mannitol in H₂O with a single catheter. The control duct on nippleB was injected with 0.50 ml of phosphate buffered saline (PBS). Amicrofuge tube was attached to the end of each catheter to collectout-flow liquid.

[0185] A duct on nipple C was injected with 0.7 ml of a 12.5% solutionof D-Mannitol in H₂O with a single catheter. The control duct on nippleC was injected with 0.70 ml of phosphate buffered saline (PBS). Amicrofuge tube was attached to the end of each catheter to collect outflow liquid.

[0186] About an hour after the fluid containing mannitol or PBS wasinjected into the ducts via the catheters, the microfuge tubes werechecked for whether any fluid was returned. The results are summarizedin the following Table III: TABLE III nipple duct solution recoverynotes A A1 0.4 ml mannitol 12.5% 310 ul liquid fluid was a milky color AA2 0.4 ml PBS none — B B1 0.5 ml mannitol 12.5% 490 ul liquid fluid wasa milky color B B2 0.5 ml PBS 240 ul liquid fluid was a milky color C C10.7 ml mannitol 12.5% 280 ul liquid fluid was a milky color C C2 0.7 mlPBS none —

[0187] Davidson green dye (1 ul) was added to each microfuge tubecontaining fluid for the purpose of taking a picture. The rabbit waseuthanized by IV injection of supersaturated KCl. PBS (1.5 ul) was addedto each collection. The cells were spun onto Shandon coated slide usingmegafunnel and cytospin-3 machine (Shandon, Inc. located in Pittsburgh,Pa.) at a speed of 1500/per minute for 15 minutes. The cells were fixedon the slide in 95% ethanol for 10 minutes. The cells were stained usingHematoxylin and Eosin (HE) method of cytology of collected fluid. Theresults of the cellular analysis are in Table IV: TABLE IV Nipple A/ductNipple B/duct Nipple B/duct Nipple C/duct A1 B1 B2 C1 A few ductal cellA few ductal cell A few ductal cell A few ductal clusters and clustersand clusters and cell clusters scattered scattered scattered scatteredand histocytes histocytes histocytes histocytes and apocrine andapocrine and apocrine and apocrine metaplastic cells metaplastic cellsmetaplastic cells metaplastic cells

[0188] The observations made from this experiment are that fluid can becollected from three out of three ducts injected with mannitol solution;that fluid could be collected from 1 out of 3 ducts injected with PBSsolution, and with approximately 50% less volume in the ducts wherefluid was collected. There were cells detected from the fluid collectedfrom each duct. The cell morphology looked similar between the mannitoland the PBS injected ducts.

[0189] All publications and patent applications cited in thisspecification are herein incorporated by reference as if each individualpublication or patent application were specifically and individuallyindicated to be incorporated by reference. Although the foregoinginvention has been described in some detail by way of illustration andexample for purposes of clarity of understanding, it will be readilyapparent to those of ordinary skill in the art in light of the teachingsof this invention that certain changes and modifications may be madethereto without departing from the spirit or scope of the appendedclaims.

What is claimed is:
 1. A method for obtaining cellular material from a human breast milk duct, said method comprising: introducing a wash fluid to the breast milk duct, wherein a volume of at least 2 ml is present within the duct for a preselected time; and collecting at least a portion of the introduced wash fluid from within the duct, wherein said portion carries the cellular material.
 2. A method as in claim 1, wherein the preselected time is less than one second.
 3. A method as in claim 1, wherein the preselected time is in the range from one second to one hour.
 4. A method as in claim 1, wherein the wash fluid is introduced to a volume of at least 2 ml prior to collecting any of wash fluid from the duct.
 5. A method as in claim 1, wherein the wash fluid is introduced to a single breast milk duct and collected from the same breast milk duct without mixing with materials from other breast milk ducts.
 6. A method as in claim 1, further comprising massaging and squeezing the breast tissue after introducing the wash fluid but prior to and during collecting a portion of the wash fluid.
 7. A method as in claim 1, further comprising separating cellular material from the collected fluid.
 8. A method as in claim 7, further comprising examining the separated cellular material.
 9. A method as in claim 1, wherein the cellular material is a substance selected from the group consisting of whole cells, cellular debris, proteins, nucleic acids, polypeptides, glycoproteins, lipids, fats, glycoproteins, small organic molecules, metabolites, and macromolecules.
 10. A method as in claim 1, wherein the wash fluid is selected from the group consisting of saline, phosphate buffered saline, a nonabsorbable fluid, an isotonic solution, an osmotic solution, a hypotonic solution, and a hypertonic solution.
 11. A method as in claim 1, wherein the wash fluid is selected from the group consisting of a protein, a colloid, a sugar, a polymer, mannitol, sorbitol, glucose, glycerol, sucrose, raffinose, fructose, lactulose, sodium chloride, polyethyleneglycol (PEG), maltodextrin, dextran (e.g. dextran 70), hydroxyethyl starch, fluid gelatin, a synthetic colloid, an antibody, a binding protein, and albumin.
 12. A method for obtaining cellular material from a human breast milk duct, said method comprising: introducing a ductal access device having at least one lumen therethrough into a duct; introducing a wash fluid through the access device lumen into the milk duct, wherein a volume of at least 2 ml is present within the duct for a preselected time; and collecting at least a portion of the wash fluid from the duct through the lumen of the access device.
 13. A method as in claim 12, further comprising massaging and squeezing the breast tissue after introducing the wash fluid but prior to and during collecting a portion of the wash fluid.
 14. A method as in claim 12, wherein introducing the ductal access device comprises positioning a distal end thereof distal to the ductal sphincter.
 15. A method as in claim 12, wherein the access device has only a single lumen which extends into the duct.
 16. A method as in claim 12, wherein the wash fluid is introduced to a volume of at least 2 ml prior to collecting any of wash fluid from the duct.
 17. A methods as in claim 12, wherein the preselected time is less than one second.
 18. A method as in claim 12, wherein the preselected time is in the range from one second to one hour.
 19. A method as in claim 12, wherein the wash fluid is introduced to a single breast milk duct and collected from the same breast milk duct without mixing with materials from other breast milk ducts.
 20. A method as in claim 12, further comprising separating cellular material from the collected fluid.
 21. A method as in claim 20, further comprising examining the separated cellular material.
 22. A method as in claim 17, wherein the cellular material is a substance selected from the group consisting of whole cells, cellular debris, proteins, nucleic acids, polypeptides, glycoproteins, lipids, fats, glycoproteins, small organic molecules, metabolites, and macromolecules.
 23. A method as in claim 12, wherein the wash fluid is selected from the group consisting of saline, phosphate buffered saline, a nonabsorbable fluid, an isotonic solution, an osmotic solution, a hypotonic solution, and a hypertonic solution.
 24. A method as in claim 12, wherein the wash fluid is selected from the group consisting of a protein, a colloid, a sugar, a polymer, mannitol, sorbitol, glucose, glycerol, sucrose, raffinose, fructose, lactulose, sodium chloride, polyethyleneglycol (PEG), maltodextrin, dextran (e.g. dextran 70), hydroxyethyl starch, fluid gelatin, a synthetic colloid, an antibody, a binding protein, and albuinin.
 25. A method for obtaining cellular material from a human breast milk duct, said method comprising: introducing a wash fluid to the breast milk duct, wherein the wash fluid is present within the duct for a preselected time; and collecting at least a portion of the introduced wash fluid from within the duct, wherein said portion carries the cellular material; wherein the wash fluid is introduced to a single breast milk duct and collected from the same breast milk duct without mixing with materials from other breast milk ducts.
 26. A method as in claim 25, wherein the volume of wash fluid is at least 2 ml.
 27. A method as in claim 25, wherein the wash fluid is introduced to a volume of at least 2 ml prior to collecting any of wash fluid from the duct.
 28. A method as in claim 25, wherein the wash fluid is introduced to a volume of at least 2 ml prior to collecting any of wash fluid from the duct.
 29. A method as in claim 25, further comprising massaging and squeezing the breast tissue after introducing the wash fluid but prior to and during collecting a portion of the wash fluid.
 30. A method as in claim 25, wherein the wash fluid is selected from the group consisting of saline, phosphate buffered saline, a nonabsorbable fluid, an isotonic solution, an osmotic solution, a hypotonic solution, and a hypertonic solution.
 31. A method as in claim 25, wherein the wash fluid is selected from the group consisting of a protein, a colloid, a sugar, a polymer, mannitol, sorbitol, glucose, glycerol, sucrose, raffinose, fructose, lactulose, sodium chloride, polyethyleneglycol (PEG), maltodextrin, dextran (e.g. dextran 70), hydroxyethyl starch, fluid gelatin, a synthetic colloid, an antibody, a binding protein, and albumin.
 32. A method as in claim 25, wherein the preselected time is less than one second.
 33. A method as in claim 25, wherein the preselected time is in a range from one second to one hour.
 34. A method as in claim 25, further comprising separating cellular material from the collected fluid.
 35. A method as in claim 34, further comprising examining the separated cellular material.
 36. A method as in claim 25, wherein the cellular material is a substance selected from the group consisiting of whole cells, cellular debris, nucleic acids, lipids, protein metabolites, small organic molecules, and macromolecules.
 37. A method for obtaining cellular material from a human breast milk duct, said method comprising: introducing a ductal access device having at least one lumen therethrough into a duct; introducing a wash fluid through the access device lumen into the milk duct, wherein the wash fluid is present within the duct for a preselected time; and collecting at least a portion of the wash fluid from the duct through the lumen of the access device; wherein the wash fluid is introduced to a single breast milk duct and collected from the same breast milk duct without mixing with materials from other breast milk ducts.
 38. A method as in claim 37, wherein the volume of wash fluid is at least 2 ml.
 39. A method as in claim 37, wherein the wash fluid is introduced to a volume of at least 2 ml prior to collecting any of wash fluid from the duct.
 40. A method as in claim 37, wherein the wash fluid is introduced to a volume of at least 2 ml prior to collecting any of wash fluid from the duct.
 41. A method as in claim 37, wherein the preselected time is less than one second.
 42. A method as in claim 37, wherein the preselected time is in a range from one second to one hour.
 43. A method as in claim 37, further comprising massaging and squeezing the breast tissue after introducing the wash fluid but prior to and during collecting a portion of the wash fluid.
 44. A method as in claim 37, wherein introducing the ductal access device comprises positioning a distal end thereof distal to the ductal sphincter.
 45. A method as in claim 37 wherein the access device has only a single lumen which extends into the duct.
 46. A method as in claim 37, further comprising separating cellular material from the collected fluid.
 47. A method as in claim 46, further comprising examining the separated cellular material.
 48. A method as in claim 37, wherein the cellular material is a substance selected from the group consisiting of whole cells, cellular debris, nucleic acids, lipids, protein metabolites, small organic molecules, and macromolecules.
 49. A method as in claim 37, wherein the wash fluid is selected from the group consisting of saline, phosphate buffered saline, a nonabsorbable fluid, an isotonic solution, an osmotic solution, a hypotonic solution, and a hypertonic solution.
 50. A method as in claim wherein the wash fluid is selected from the group consisting of a protein, a colloid, a sugar, a polymer, mannitol, sorbitol, glucose, glycerol, sucrose, raffinose, fructose, lactulose, sodium chloride, polyethyleneglycol (PEG), maltodextrin, dextran (e.g. dextran 70), hydroxyethyl starch, fluid gelatin, a synthetic colloid, an antibody, a binding protein, and albumin.
 51. A kit comprising: a ductal access device; and instructions for use setting forth a method according to claim
 12. 52. A ductal access device comprising: an access tube having a distal end, at least one lumen therethrough, and dimensions which permit introduction of the distal end through a ductal orifice and positioning a distal end thereof distal to the ductal sphincter of a human breast.
 53. A ductal access device as in claim 52, further comprising means on the access tube for positioning the distal end distal to the ductal sphincter.
 54. A ductal access device as in claim 53, wherein the positioning means comprises length indicia on the tube which permit a user to determine the depth to which the distal end of the tube has been introduced.
 55. A ductal access device as in claim 53, wherein the positioning means comprises a stop element formed or attached to the tube, wherein the stop has dimensions which prevent further insertion of the tube into the duct and wherein the stop is positioned on the tube so that the distal tip will be located distal to the ductal sphincter when the device is fully inserted up to the stop.
 56. A ductal access device as in claim 55, wherein the stop element comprises a collar affixed to or formed on an exterior surface of the tube.
 57. A ductal access device as in claim 52, further comprising means for anchoring the device to the breast.
 58. A ductal access device as in claim 52, further comprising a receiving portion comprising a water tight seal for receiving the dilator.
 59. A ductal access device as in claim 55, wherein the stop element comprises a hub attached to a proximal end of the tube, wherein the hub has a width which is greater than the diameter of the tube so that a shoulder is formed at a junction between the tube and the hub.
 60. A ductal access device as in claim 53, wherein the positioning means comprises a nob on the access tube having an increase diameter for anchoring the tube distal to the ductal sphincter once the nob has passed the sphincter and rests distal to it.
 61. A ductal access device as in claim 52, wherein the access tube has an outer diameter of 0.05 inches or 1.27 mm or less.
 62. A ductal access device as in claim 52, wherein the access tube has an outer diameter of 0.010 inches (or 0.254 mm) or greater.
 63. A ductal access device as in claim 53, wherein the outer diameter is in the range from 0.010 inches or 0.254 mm to 0.050 inches or 1.27 mm.
 64. A ductal access device as in claim 52, wherein the access tube has a lumen diameter 0.007 inches (or 0.178 mm) or greater.
 65. A ductal access device as in claim 52, wherein the access tube has a lumen diameter in the range from 0.007inches or 0.178 mm to 0.047 inches or 1.19 mm.
 66. A ductal access device as in claim 52, further comprising: an infusion connector providing a fluid flow path into the lumen of the tube; and a collection connector providing a fluid outlet path from the lumen of the tube, said infusion and collection connectors being isolated from each other so that the fluid may be infused through the infusion connector and simultaneously removed through the collection connector.
 67. A ductal access device as in claim 52, further comprising a dilator removably received in the access tube and having a distal tip which is positionable through the access tube to extend from the distal end thereof.
 68. A ductal access device as in claim 67, wherein the dilator has an outer diameter of 0.024 inches (or 0.61 mm) or less.
 69. A ductal access device as in claim 67, wherein the dilator is tapered.
 70. A ductal access device as in claim 67, wherein a receiving portion of the device for receiving the dilator comprises a water-tight seal.
 71. A ductal access system comprising: a ductal access device as in claim 52; and a container holding a premeasured volume of ductal wash fluid.
 72. A ductal access system as in claim 71, wherein the container comprises a syringe for connection to the first side port.
 73. A ducal access system as in claim 71, wherein the pre-measured volume is in the range from 2 ml to 100 ml.
 74. A ductal access system as in claim 71, wherein the ductal access fluid is selected from the group consisting of saline, phosphate buffered saline, a nonabsorbable fluid, an isotonic solution, an osmotic solution, a hypotonic solution, and a hypertonic solution.
 75. A ductal access system as in claim 71, wherein the ductal access fluid is selected from the group consisting of a protein, a colloid, a sugar, a polymer, mannitol, sorbitol, glucose, glycerol, sucrose, raffinose, fructose, lactulose, sodium chloride, polyethyleneglycol (PEG), maltodextrin, dextran (e.g. dextran 70), hydroxyethyl starch, fluid gelatin, a synthetic colloid, an antibody, a binding protein, and albumin.
 76. A ductal access device comprising: an access tube having a distal end, a single lumen therethrough, and dimensions which permit introduction of the distal end through a ductal orifice and positioning a distal end thereof distal to the ductal sphincter; an infusion connector providing a fluid flow path into the lumen of the access tube; and a collection connector providing a fluid outlet path from the lumen of the access tube, said infusion and collection connectors being isolated from each other so that fluid may be infused through the infusion connector and simultaneously removed through the collection connector.
 77. A ductal access device as in claim 76, wherein the tube has an outer diameter of 0.010 inches or 0.254 mm or greater.
 78. A ductal access device as in claim 76, wherein the tube has an outer diameter of 0.050 inches or 1.27 mm or less.
 79. A ductal access device as in claim 77, wherein the outer diameter is in the range from 0.010 inches or 0.254 mm to 0.050 inches or 1.27 mm.
 80. A ductal access device as in claim 76, wherein the access tube has a lumen diameter 0.007 inches or 0.178 mm or greater.
 81. A ductal access device as in claim 79, wherein the access tube has a lumen diameter in the range from 0.007 inches or 0.178 mm to 0.047 inches or 1.1.9 mm.
 82. A ductal access device as in claim 76, further comprising means on the access tube positioning a distal end thereof distal to the ductal sphincter.
 83. A ductal access device as in claim 82, wherein the positioning means comprises length indicia on the tube which permit a user to determine the depth to which the distal end of the tube has been introduced.
 84. A ductal access device as in claim 82, wherein the positioning means comprises a stop element formed or attached to the tube, wherein the stop has dimensions which prevent further insertion of the tube into the duct and wherein the stop is positioned on the tube so that a distal end of the distal tip is positioned thereof distal to the ductal sphincter.
 85. A ductal access device as in claim 84, wherein the stop element comprises a collar affixed to or formed on an exterior surface of the tube.
 86. A ductal access device as in claim 84, wherein the stop element comprises a hub attached to a proximal end of the tube, wherein the hub has a width which is greater than the diameter of the tube so that a shoulder is formed at a junction between the tube and the hub.
 87. A ductal access device as in claim 82, wherein the positioning means comprises a nob on the access tube having an increase diameter for anchoring the tube distal to the ductal sphincter once the nob has passed the sphincter and rests distal to it.
 88. A ductal access device as in claim 76, further comprising means for anchoring the device to the breast.
 89. A ductal access device as in claim 76, further comprising a dilator removably received in the access tube and having a distal tip which is positionable through the access tube to extend from the distal end thereof.
 90. A ductal access device as in claim 89, wherein the dilator has an outer diameter of 0.024 inches (or 0.061 mm) or less.
 91. A ductal access device as in claim 89, wherein the dilator is tapered.
 92. A ductal access device as in claim 89, wherein a receiving portion of the device for receiving the dilator comprises a water-tight seal.
 93. A ductal access system comprising: a ductal access device as in claim 76; and a container holding a premeasured volume of ductal wash fluid.
 94. A ductal access system as in claim 93, wherein the ductal wash fluid is selected from the group consisting of a protein, a colloid, a sugar, a polymer, mannitol, sorbitol, glucose, glycerol, sucrose, raffinose, fructose, lactulose, sodium chloride, polyethyleneglycol (PEG), maltodextrin, dextran (e.g. dextran 70), hydroxyethyl starch, fluid gelatin, a synthetic colloid, an antibody, a binding protein, and albumin.
 95. A ductal access system as in claim 93, wherein the container comprises a syringe for connection to the first side port.
 96. A ductal access system as in claim 93, wherein the premeasured volume is in the range from 2 ml to 100 ml.
 97. A ductal access system as in claim 93, wherein the ductal access fluid is selected from the group consisting of saline, phosphate buffered saline, a nonabsorbable fluid, an isotonic solution, an osmotic solution, a hypotonic solution, and a hypertonic solution.
 98. A ductal access device comprising: a hub having an internal elongate manifold, a lower port at a bottom of the manifold, and first and second side ports spaced above the lower port; and an access tube having a distal end, a proximal end, a lumen therethrough, and dimensions which permit introduction of the distal end through a ductal orifice and a positioning a distal end thereof distal to the ductal sphincter of the human breast, wherein the proximal end of the tube is attached to the lower port of the hub.
 99. A ductal access device as in claim 98, wherein the first and second side ports are at the same level relative to the lower port.
 100. A ductal access device as in claim 98, wherein the first side port is below the second side port.
 101. A ductal access device as in claim 98, wherein the access tube has an outer diameter of 0.010 inches or 0.245 mm or greater.
 102. A ductal access device as in claim 98, wherein the access tube has an outer diameter of 0.50 inches or 1.27 mm or less.
 103. A ductal access device as in claim 101, wherein the outer diameter is in the range from 0.010 inches or 0.245 mm to 0.050 inches or 1.27 mm.
 104. A ductal access device as in claim 103, wherein the access tube has a lumen diameter 0.007 inches (0.178 mm) or greater.
 105. A ductal access device as in claim 103, wherein the access tube has a lumen diameter in a range from 0.007 inches (0.178 mm) to 0.047 inches (1.19 mm).
 106. A ductal access device as in claim 98, further comprising: an infusion tube connected to the first port of the hub; and a collection tube connected to the second port of the hub.
 107. A ductal access device as in claim 98, wherein the manifold has a volume in the range from 0.01 cc to 1.0 cc.
 108. A ductal access device as in claim 98, wherein the first side port is spaced above the lower port by a distance less than 5 mm and the second side port is spaced above the first side port by a distance in the range from 0.10 mm to 5 mm.
 109. A ductal access device as in claim 98, further comprising a dilator removably received in the hub and having a distal tip which is positionable through the access tube to extend from the distal end thereof.
 110. A ductal access device as in claim 109, wherein the dilator has an outer diameter of 0.024 inches (or 0.061 mm) or less.
 111. A ductal access device as in claim 109, wherein the dilator is positionable through the hub manifold and into the lumen of the access tube.
 112. A ductal access device as in claim 109, wherein the dilator is tapered.
 113. A ductal access device as in claim 109, wherein a receiving portion of the hub for receiving the dilator comprises a water-tight seal.
 114. A ductal access device as in claim 98, further comprising means on the access tube for positioning the distal end of the access tube distal to the ductal sphincter.
 115. A ductal access device as in claim 114, wherein the positioning means comprises length indicia on the tube which permit a user to determine the depth to which the distal end of the tube has been introduced.
 116. A ductal access device as in claim 114, wherein the positioning means comprises a stop element formed or attached to the tube, wherein the stop has dimensions which prevent further insertion of the tube into the duct and wherein the stop is positioned on the tube so that the distal tip will be located distal to the ductal sphincter when the device is fully inserted up to the stop.
 117. A ductal access device as in claim 116, wherein the stop element comprises a collar affixed to or formed on an exterior surface of the tube.
 118. A ductal access device as in claim 116, wherein the stop element comprises a hub attached to a proximal end of the tube, wherein the hub has a width which is greater than the diameter of the tube so that a shoulder is formed at a junction between the tube and the hub.
 119. A ductal access device as in claim 98, further comprising means for anchoring the device to the breast.
 120. A ductal access device as in claim 114, wherein the positioning means comprises a nob on the access tube having an increase diameter for anchoring the tube distal to a ductal sphincter once the nob has passed the sphincter and rests distal to it.
 121. A ductal access system comprising: a ductal access device as in claim 98; and a container holding a premeasured volume of ductal wash fluid.
 122. A ductal access system as in claim 121, wherein the container comprises a syringe for connection to the first side port.
 123. A ducal access system as in claim 121, wherein the pre-measured volume is in the range from 2 ml to 100 ml.
 124. A ductal access system as in claim 121, wherein the ductal access fluid is selected from the group consisting of saline, phosphate buffered saline, a nonabsorbable fluid, an isotonic solution, an osmotic solution, a hypotonic solution, and a hypertonic solution.
 125. A ductal access system as in claim 121, wherein the ductal access fluid is selected from the group consisting of a protein, a colloid, a sugar, a polymer, mannitol, sorbitol, glucose, glycerol, sucrose, raffinose, fructose, lactulose, sodium chloride, polyethyleneglycol (PEG), maltodextrin, dextran (e.g. dextran 70), hydroxyethyl starch, fluid gelatin, a synthetic colloid, an antibody, a binding protein, and albumin.
 126. A ductal access catheter comprising: a catheter body having a distal end and a proximal end and including at least a distal portion and a proximal portion; wherein the distal portion has a cross-sectional geometry which can be inserted through a ductal orifice into a ductal lumen of a human breast; wherein the proximal portion has a cross-sectional geometry which inhibits insertion through the ductal orifice and into the ductal lumen; and wherein the catheter body has at least an infusion lumen and an collection lumen each of which has a distal port near a distal end of the distal portion and a proximal connector near a proximal end of the proximal portion.
 127. A ductal access catheter as in claim 126, wherein the distal portion of the catheter body is stiffened over at least a part of its length to facilitate insertion through the ductal orifice and into the ductal lumen.
 128. A ductal access catheter as in claim 127, wherein the stiffened distal portion of the catheter body has an average bending stiffness in the range from about 0.010 inch-lbs to about 0.50 inch-lbs.
 129. A ductal access catheter as in claim 127, further comprising a stiffening member disposed in the distal portion of the catheter body.
 130. A ductal access catheter as in claim 126, wherein the distal portion of the catheter body has a maximum width in the range from 0.008 inches (0.020 mm) to 0.035 inches (0.089 mm) and the proximal portion of the catheter body has a minimum width in the range from 0.010 inches (0.0254 mm) to 0.100 inches (0.254 mm).
 131. A ductal access catheter as in claim 130, wherein the distal portion of the catheter body has a generally tubular structure with a diameter in the range from 0.008 inches (0.020 mm) to 0.035 inches (0.089 mm) and the proximal portion of the catheter body has a generally tubular structure with a diameter in the range from 0.030 inches (0.076 mm) to 0.10 inches (0.254 mm) and wherein the proximal diameter is greater than the distal diameter by at least 0.010 inches.
 132. A ductal access catheter as in claim 126, wherein at least one of the distal collection port and the distal infusion portion are disposed on a side of the distal portion of the catheter body.
 133. A ductal access catheter as in claim 132, wherein the distal collection port and the distal infusion port are both located on the side of the distal portion of the catheter body.
 134. A ductal access catheter as in claim 133, wherein the distal collection port and the distal infusion port are axially aligned.
 135. A ductal access catheter as in claim 133, wherein the distal collection port and the distal infusion port are axially spaced apart.
 136. A ductal access catheter as in claim 133, wherein the catheter body includes an atraumatic distal tip.
 137. A ductal access catheter as in claim 136, wherein the tip is composed of a soft polymeric material, has a diameter in the range from about 0.008 inches (0.020 mm) to about 0.035 inches (0.089 mm), and a length at least 0.25 cm.
 138. A ductal access catheter comprising: a catheter body having a distal end and a proximal end and including at least a distal portion and a proximal portion; wherein the distal portion has a cross-sectional geometry which can be inserted through a ductal orifice into a ductal lumen of a human breast; wherein the distal portion of the catheter body is stiffened over at least a part of its length to facilitate insertion through the ductal orifice and into the ductal lumen; and wherein the catheter body has at least an infusion lumen and an collection lumen each of which has a distal port near a distal end of the distal portion and a proximal connector near a proximal end of the proximal connector.
 139. A ductal access catheter as in claim 138, wherein the stiffened distal portion of the catheter body has an average bending stiffness in the range from about 0.010 inch-lbs to about 0.50 inch-lbs.
 140. A ductal access catheter as in claim 138, wherein the proximal portion has a cross-sectional geometry which inhibits insertion through the ductal orifice and into the ductal lumen.
 141. A ductal access catheter comprising: a catheter body having a distal end and a proximal end and including at least a distal portion and a proximal portion; wherein the distal portion has a cross-sectional geometry which can be inserted through a ductal orifice into a ductal lumen of a human breast; and wherein the catheter body has at least an infusion lumen and an collection lumen each of which has a distal port near a distal end of the distal portion and a proximal connector near a proximal end of the proximal connector; and wherein the distal collection port and the distal infusion port are both located on the side of the distal portion of the catheter body.
 142. A ductal access catheter as in claim 141, wherein the distal collection port and the distal infusion port are axially aligned.
 143. A ductal access catheter as in claim 141, wherein the distal collection port and the distal infusion port are axially spaced apart.
 144. A ductal access catheter as in claim 141, wherein the proximal portion has a cross-sectional geometry which inhibits insertion through the ductal orifice and into the ductal lumen.
 145. A method for lavage of a ductal network in a human breast, said method comprising: providing a catheter as in claim 127; inserting the distal portion of the catheter through a ductal orifice and into a distal lumen of the ductal network; introducing a wash fluid through the infusion lumen into the ductal network; and withdrawing the wash fluid and substances borne by the wash fluid from the ductal network through the collection lumen.
 146. A ductal access system comprising: a catheter as in claim 127, and instructions for use setting forth a method for lavage of a ductal network in a human breast including introducing a wash fluid through the infusion lumen into the ductal network and withdrawing the wash fluid and substances borne by the wash fluid from the ductal network through the collection lumen.
 147. A device as in claim 52, further comprising a means for controlling a flow of fluid through the infusion lumen.
 148. A device as in claim 52, further comprising a means for controlling a flow of fluid through the collection lumen.
 149. A device as in claim 52, further comprising both a means for controlling a fluid flow through the infusion lumen and a means for controlling a fluid flow through the collection lumen.
 150. A device as in claim 149, wherein the fluid control means comprise compressable lumens.
 151. A device as in claim 149, wherein the fluid control means comprise stopcocks on each lumen.
 152. A device as in claim 106, further comprising a means for controlling a flow of fluid through the infusion tube.
 153. A device as in claim 106, further comprising a means for controlling a flow of fluid through the collection tube.
 154. A device as in claim 106, further comprising both a means for controlling a fluid flow through the infusion lumen and a means for controlling a fluid flow through the collection lumen.
 155. A device as in claim 154, wherein the fluid control means comprise compressable lumens.
 156. A device as in claim 154, wherein the fluid control means comprise stopcocks on each lumen.
 157. A method for increasing an amount of fluid collectable from a milk duct of a breast of a mammal comprising administering an agent to a ductal lumen of a breast capable of maintaining or increasing the amount of collectable fluid in the ductal lumen, and collecting the fluid from the duct.
 158. The method of claim 157, wherein the agent comprises an agent selected from the group consisting of a nonabsorbable agent, an oncotic agent and an osmotic agent.
 159. The method of claim 157, wherein the agent is soluble.
 160. The method of claim 157, wherein the agent comprises a molecule selected from the group consisting of a protein, a colloid, a sugar, and a polymer.
 161. The method of claim 160, wherein the agent comprises a protein and the protein is selected from the group consisting of a binding protein and an antibody.
 162. The method of claim 161, wherein the protein is a binding protein, and the binding protein comprises albumin.
 163. The method of claim 157, wherein the agent comprises an agent selected from the group consisting of mannitol, sorbitol, glucose, glycerol, sucrose, raffinose, fructose, lactulose, sodium chloride, albumin, polyethyleneglycol (PEG), maltodextrin, dextran (e.g. dextran 70), hydroxyethyl starch, fluid gelatin, and a synthetic colloid.
 164. The method of claim 157, wherein administering comprises administering locally.
 165. The method of claim 164, wherein administering locally comprises administering intraductally. 